Adobe Systems Lékařská fakulta Masarykovy univerzity 1 Antifungals (antimycotics) MUDr. Alena Máchalová, Ph.D. Adobe Systems Antimycotics §Chemotherapeutics for the treatment od infections caused by pathogenic fungi: § incidence: immunodefficiency, DM, radiotherapy, chemotherapy, HIV, transplantations Mycotic infections: §superficial (local) - skin and mucous membranes §systemic infections - individuals with weakened immunity (therapy with ATB, CHT, cytostatics,...) § § [USEMAP] Adobe Systems Superficial mycoses Dermatomycoses ̶ trychophyton ̶ epidermophyton ̶ microsporum ̶ dermatophyton (tinea) ̶ Superficial candidiasis Skin, nails and mucosae (oral cavity, vagina), infections caused by Candida yeasts (most often Candida albicans). ü ̶ ̶ ̶ ü ̶ [USEMAP] Adobe Systems Adobe Systems Definujte zápatí - název prezentace / pracoviště 5 Dermatophytes Tinea corporis (ringworm), includes tinea gladiatorum and tinea faciei Tinea capitis (ringworm of the scalp) Tinea cruris (jock itch) Tinea pedis (athlete's foot) Tinea unguium (onychomycosis) Tinea manuum (commonly presents with “one-hand, two-feet” involvement) Tinea barbae (beard infection in male adolescents and adults) Tinea incognito (altered appearance of dermatophyte infection caused by topical steroids) Candida (yeast) and mold, which may cause onychomycosis or coexist in a dystrophic nail Pityriasis versicolor (formerly tinea versicolor) caused by Malassezia species Uncommon fungal skin infections that involve other organs (e.g., blastomycosis, sporotrichosis) Fungal Infections of the Skin Adobe Systems Systemic mycoses ̶ ‒Lung aspergilosis ‒Pneumocystis pneumonia (P.carini) ‒Legionella pneumonia ‒ ‒Cryptocococal meningitis and endocarditis ‒Rhinocerebral mucomycose ̶Systemic candidiasis ü ̶ ̶ ̶ ü ̶ Obsah obrázku fotka, vsedě, talíř, stůl Popis byl vytvořen automaticky [USEMAP] Risk factors for invasive candidiasis Iatrogenic factors Factors of the patient > 3 antibiotics chronic neutropenia > 4 days at ICU immunosuppression > 2 days on ventilator DM central venous catheter colonization by candida parenteral nutrition elderly person abdominal surgery Adobe Systems The most common agents of mycotic infections Yeasts Candida species C.albicans 50-80% C.tropicalis C.krusei C.glabrata C.parapsilosis C.lusitaniae Moulds Aspergillus sp. A.fumigatus 80-90 % A.flavus 10-15 % A.terreus 2-5 % A.niger Adobe Systems The treatment of fungal infections ̶curing deep tissue mycosis is difficult; patient may die even if given modern effective antifungals ̶ ̶treatment may last up to 4-6 weeks ̶ ̶surgical resection of the most affected focus may be required [USEMAP] Adobe Systems Definujte zápatí - název prezentace / pracoviště 10 Mechanism of action of antifungals ‒ Specific - interfering at a defined place of micromycet metabolism ‒ Nonspecific - they usually work also on bacteria and can be considered antifugical antiseptics ‒ ‒ Blockage of synthesis fungal lipid (ergosterol) in cell membranes [USEMAP] Adobe Systems ANTIMYCOTICS squalene oxidosqualene lanosterol Ergosterol 1-3 glukan squalenepoxidase lanosterol-14a -demethylase AZOLES ALLYLAMINES POLYENES ECHINOCANDINS HYDROXYPYRIDONE DERRIVATIVE ENZYME ACTIVITY REDOX STABILITY GENETIC INFORMATION Ciclopirox [USEMAP] Adobe Systems http://www.doctorfungus.org/thedrugs/images/drug-targets.jpg Definujte zápatí - název prezentace / pracoviště 12 Mechanism of action of antifungals Inhibition Inhibition Inhibition Adobe Systems Classification of antifungals according to the mechanism of action [USEMAP] Classification of antifungals Polyenes systemic amphotericin B local nystatin, natamycin Antimetabolites systemic flucytosine Azoles systemic fluconazole, itrakonazole vorikonazole posakonazole local clotrimazole, ekonazole, oxikonazole, terkonazole,… Echinocandines systemic caspofungin, anidulafungin others systemic Alylamines - terbinafin, griseofulvin local ciclopiroxolamin, tolnaftate [USEMAP] Adobe Systems Polyenes Nystatin Natamycin Amphotericin B Adobe Systems Systemic polyenes ̶Amphotericin B §broadest spectrum, lowest resistance §toxic, most of patients percieve some grade of toxicity/AE §drug of choice in aspergiloses § MoA: binding to ergosterol in cell wall ̶ ̶ I: severe mycotic infections (life theratening), „prophylactic“ use in oncologic treatment, after trasplantations… [USEMAP] Adobe Systems Amphotericin B PK: §poor GIT bioabailability, administered i.v.- lipidic complex (ABLC) §difficult distribution to tissues (HEB) §binding to proteins (95%) and cholesterol §T1/2 15 days! ̶ Toxicity §Acute manifestations: §fever, chills, rigor, nausea, vomiting, §tachycardia, hypotension, bronchospasm §headache, muscle pain, joint pain, §allergies, §thrombophlebitis ̶ ̶ §Chronic manifestations: §nephrotoxicity (total dose) followed by electrolyte imbalance, §neuropathy §normocytic normochromic anemia (therapy: erythropoietin) §trombocytopenia Prevention of toxicity: §Liposomes - ¯nefrotoxicity § §3 prep: §Amfotericin B lipid complex (Abelcet) §Liposomální Amfotericin B (Ambisom) §Koloid dispersion of amphotericin B (Amphocil) § §Premedication: §Hydratation §Paracetamol §Antihistamines §Cortikosteroids [USEMAP] Adobe Systems Definujte zápatí - název prezentace / pracoviště 18 18 Topical polyenes Nystatin (fungicidin): I: superficial mycoses, yeasts, the most often used antifungal drug in oral medicine Fungicidin, Macmiror Natamycine: I: Candida, Trichomonas vaginalis, anguli infectiosi, vulvitis, onychomycoses Pimafucin, Pimafucort Obsah obrázku text Popis byl vytvořen automaticky Obsah obrázku jídlo Popis byl vytvořen automaticky Obsah obrázku text Popis byl vytvořen automaticky [USEMAP] Antimetabolites Flucytosin Adobe Systems Definujte zápatí - název prezentace / pracoviště 20 Antimetabolites Flucytosine (5-fluorocytosine) §Systemic effects, narrow spectrum – candida, cryptococcus §Good penetration into tissues (HEB, placenta, breast milk) – genotoxic, teratogenous § MoA: inhibition of nucleic acid synthesis §fungistatic §Monotherapy is rarely used - Synergism with amphotericin B and azoles AE: granulocytopenia, GIT intolerance genotoxic, teratogenous [USEMAP] Adobe Systems Triazoles Definujte zápatí - název prezentace / pracoviště 21 Ketokonazole Mikonazole Fluconazole Posaconazole Itraconazole Voriconazole Clotrimazole Ekonazole Oxiconazole Fenticonazole Tioconazole Imidazoles Systemic Local Azoles Dermacologics and gynecologics, are not absorbed AE: irritation, contact allergies Systemic candidoses Systemic candidoses Systemic aspergilloses [USEMAP] Adobe Systems azole target Definujte zápatí - název prezentace / pracoviště 22 Azoles ̶MoA: ̶inhibition of C-14-α-demethylase (CYP450) ̶CYP and Pgp inhibition !!! - interactions + AE ̶ [USEMAP] Adobe Systems Definujte zápatí - název prezentace / pracoviště 23 Azoles Ketoconazole §accumulation in the skin (5 days after discontinuation) §p.o., skin, hair and nail infections (dermatophytes and yeasts) §for the treatment of endogenous Cushing's syndrome Flukonazol §p.o. i.v., §the only hydrophilic – excretion in urine § the highest therapeutic index, the least AE (GIT, allergies, headaches), DDI §Great clinical experience, very often used also in children Obsah obrázku text Popis byl vytvořen automaticky [USEMAP] Adobe Systems Definujte zápatí - název prezentace / pracoviště 24 Azoles Itraconazole p.o., variable absorption, 1st pass effect, β-cyclodextrin i.v. high antifungal specificity incl. Aspergillus), does not penetrate into the CNS AE: increased liver enzymes, skin reactions ̶ Adobe Systems Definujte zápatí - název prezentace / pracoviště 25 Azoles Voriconazole - Better effect in invasive aspergillosis than amphoterecin B - p.o. and i.v., almost complete F (95-96%) - High fungicidal aktivity– candida, aspergillus - invasive life-threatening infections (aspergillosis, mucormycosis) candidoses rezistant to fluconazole Posaconazole - second-line drug - prohylaxis of candidiasis in risk patients, aspergillosis resistant to AmB or itraconazole, or in intolerance of 1st line drugs ̶ Obsah obrázku text Popis byl vytvořen automaticky [USEMAP] Adobe Systems Definujte zápatí - název prezentace / pracoviště 26 Topical (local) azoles ̶Clotrimazole (depot in stratum corneum) ̶Econazole (also efficient against some bacterias) ̶Oxiconazole, Fenticonazole, Tioconazole Dermacologics and gynecologics, are not absorbed AE: irritation, contact allergies ̶ [USEMAP] Allylamines Terbinafine terbinafin Adobe Systems ANTIMYCOTICS squalene oxidosqualene lanosterol Ergosterol 1-3 glukan squalenepoxidase lanosterol-14a -demethylase AZOLES ALLYLAMINES POLYENES ECHINOCANDINS HYDROXYPYRIDONE DERRIVATIVE ENZYME ACTIVITY REDOX STABILITY GENETIC INFORMATION Ciclopirox [USEMAP] Adobe Systems 29 Allylamines Terbinafine MoA: block of squalenepoxidase ̶acummulation in the adipose tissue and skin ̶fungicidal activity up to 3 w after discont. ̶synergistic effect with ketoconazole AE: dyspepsia, loss of apetite I: tinea, candidiasis, onychomycosis ̶ [USEMAP] Adobe Systems Echinocandins = lipopeptides ̶Caspofungin (Cancidas) ̶Invazivní kandidóza, aspergilóza ̶Micafungin (Mycamine) ̶Invazivní kandidóza ̶Anidulafungin (Ecalta) ̶Invazivní kandidóza [USEMAP] Anidulafungin | CAS 166663-25-8 | SCBT - Santa Cruz Biotechnology Echinocandins MoA: inhibition of 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 invasive mycoses (aspergillosis, invasive candidiasis) 1st choice in hemodynamic instable patient with severe infection AE: minimal toxicity, flebitis, GIT AE, hypokalemia [USEMAP] cílové místo působení echinokandinů není přítomno v buňce savců - minimální toxicita Echinocandins comprise a ring of six amino acids linked to a lipophilic side-chain. All drugs in this group are synthetic modifications of echinocandin B, which is found naturally in Aspergillus nidulans. Caspofungin active in vitro against a wide variety of fungi, and it has proved effective in the treatment of candidiasis and forms of invasive aspergillosis that are refractory to amphotericin. Oral absorption is poor, and it is given intravenously, once daily. Anidulafungin is used mainly for invasive candidiasis; again it is given intravenously. The principal side effects of both drugs include nausea, vomiting and diarrhoea, and skin rash. The relatively new micafungin is also mainly used for treating invasive candidiasis. It shares many of the side effects of the group but may also cause serious hepatotoxicity Adobe Systems Other antifungal drugs Ciklopirox(-olamin) Tolnaftate (Griseofungin) Adobe Systems Ciclopirox-olamine topical fungicidal antimycotic agent + G+/G- bacteria, mycoplasms, trichomonades MoA: chelates Fe3+ (➨ metaloproteins function abruption) ➨ i. cytochrome – blocks energy metabolism of the mycotic cell ➨ inh. catalase, peroxidase – block antioxidative protection Cytoplasmatic membrane – block of transporters - deplete essent. AA (Leu), nucleotides, .. antioxidant - scavenger ROS (OH•) inhibitor AA ➨ inh. synthesis a LT in human PMN cells antiinflammatory activity in vivo [USEMAP] birch tar –betulae beech tar – fagi pix Adobe Systems Tolnaftate OTC drug for the treatment of tinea pedis, tinea cruris, dermatophytosis Fungicid MoA similar to terbinafine birch tar –betulae beech tar – fagi pix Adobe Systems Griseofulvin obsolent Narrow spectrum, fungistatic MA: interaction with microtubules – mitotic poison • administered orally • • acummulation in stratum corneum, hair, nails • • I: dermatomycoses AE: GIT irritation, alergy, leucopenia, hepatotoxicity, nerologic disorders CYP inducer dermatophyte infections of the skin, hair, and nails not adequately treated by topical therapy isolated from cultures of Penicillium griseofulvum. It interferes with mitosis by binding to fungal microtubules. It can be used to treat dermatophyte infections of skin or nails when local administration is ineffective, but treatment needs to be prolonged. It has largely been superseded by other drugs. The plasma half-life is 24 h, but it is retained in the skin for much longer. It potently induces cytochrome P450 enzymes and causes several clinically important drug interactions Adobe Systems ANTIMYCOTICS Nonspecific antifungals 1) Acids and derivatives: Ac. salicylicum Ac. boricum Ac. undecylenicum Ac. benzoicum 2) Phenols: resorcinol, hexachlorophene 3) Organic dyes: • crystal gentian - (Methylrosanilinii chloridum) • methylene blue - (Methylthioninii chloridum) • brilliant green - (Viride nitens) [USEMAP] Adobe Systems ANTIMYCOTICS Nonspecific anfufungals 4) Aldehydes: formaldehyde, glutaraldehyde 5) Halogens and derivatives: iodine, iodine-povidon, iodine-glycerol chlorine 6) Oxidizing agents: KMnO4 , H2O2 (1-3%) 7) Tars: Lithanthracis pix Betulae pix Fagi pix… birch tar –betulae beech tar – fagi pix