By Howard Roberts,2014-09-04 04:42
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SYSTEMIC ANTIFUNGAL DRUGS FOR SYSTEMIC INFECTION AMPHOTERICN B PREPARATIONS: 1. Colloidal suspension of amphotericin B & Na deoxycholate (DOC) IV ; 50 mg amphotericin B, 41 mg deoxycholate ; Addition of electrolyte to infusion solution causes colloid to aggregate 2. Amphotericin B Colloidal Dispersion ; contains roughly equimolar amounts of Amphotericin B & cholesteryl sulfate ; Forms a colloidal solution when dispersed in aqueous solution 3. Unilamellar Vessicle Formulation Amphotercin B 50 mg + 350 mg of lipid in 10% molar ratio 4. Amphotericin B Lipid Complex Amphotericin B 35% + dimyristolphosphatidylcholine & glycerol ANTIFUNGAL ACTIVITY: - Candida sp., C. neoformans, B. dermatidis, H. capsulatum, Sporothrix schenkii, C. immitis, Paracoccidioides brazilienzes, Aspergillus sp., Penicilium marneffei, Mucormycosis - Limited activity to Leishmania, braziliensis, Naegleria fowleri - No antibacterial activity AMPHOTERICN B PHARMACOKINETICS: MECHANISM OF ACTION: THERAPEUTIC USES: ADVERSE REACTIONS: NOTES - Poorly absorbed from the GIT - Antifungal activity depends - Candida esophagitis - INFUSION-RELATED - Discovered by Gold & - Oral preparation is only on the binding with - Meningitis caused by TOXICITY: fever & chills, coworkers in 1956 effective in fungi within the ERGOSTEROL coccidioides muscle spasms, vomiting, - Produced by Streptomyces lumen of the GIT - Alters the permeability of the - Mucormycoses headache, & hypotension nodosus - Serum t ? is 15 days cell by forming amphotericin - Invasive aspergillosis - SLOWER TOXICITY: renal - Heptane macrolide w/ 7 - Widely distributed in tissues B associated pores in the cell - Extracutaneous sporothrichosis damage conjugated double bonds in the - 2-3% CSF concentration membrane - Cryptococcosis ; Reversible renal trans position & 3-amino-3,6- - Combines with lipids along - Candida cystitis injury dideoxymannose connected to the double rich bond & - Mycotic corneal ulcers & ; Irreversible renal the main ring by a glycoside associates with H2O keratitis injury- renal tubular bond molecules along the OH-rich injury - Amphotericin polyene side macrolide - Pores allow leakage of - Nearly insoluble in water intracellular ions & macromolecules ;CELL DEATH FLUCYTOSINE (5-FC) PHARMACOKINETICS MECHANISM OF ACTION: CLINICAL USE: ADVERSE EFFECTS: NOTES - Available in oral preparation - Taken up by fungal cells via - Cryptococcal meningitis - Leukopenia & - Discovered in 1957 - Well absorbed (>90%) with CYTOSINE PERMEASE - Candida species thrombocytopenia - Fluorinated pyrimidine related serum - Converted intracellularly to 5 - Dermatiaceous molds that cause - Rash to florouracil & floxuridine - Concentration peaking 1-2 hrs FU 5-fluorodeoxyuridine chromoblastomycosis - Nausea/vomiting, diarrhea, - Spectrum of activity is narrower - Poorly protein bound monophosphate & 5-severe enterocolitis than that of amphotericin - Penetrates well body fluids & fluorouridine triphosphate CSF ;inhibit RNA & DNA - T ? is 3-4 hrs synthesis AZOLES: IMIDAZOLES TRIAZOLES - Ketoconazole - Itraconazole



    IMIDAZOLES TRIAZOLES - Miconazole - Fluconazole - Clotrimazole - Voriconzaole MECHANISM OF ACTION: CLINICAL USES: THERAPEUTIC USES: ADVERSE REACTIONS: DRUG INTERACTIONS: - Inhibition of sterol 14 α-- Candida species - Blastomycosis, histoplasmosis, - Dose-dependent anorexia, - Increases cyclosporine levels demethylase - Cryptococcus neoformans coccidiodomycosis, nausea, vomiting - Enhances arrythmogenic - Impair the biosynthsesis of - Endemic mycoses pseudallescheriasis - Inhibits steroid biosynthesis in effects of cissapride ergosterol for the cytoplasmic - Paracoccidiodomycosis, patients endocrine - H2 antagonists increases membrane;accumulation of ringworm, tinea versicolor, abnormalities gastric pH, interfer with the 14-α-methylsterols chronic mucocutaneous absorption of ketoconazole - Impairing functions of candidiasis - Rifamycins increased hepatic membrane bound enzymes such - Candida vulvovaginitis, oral & metabolism as ATPase & enzymes of esophageal candidiasis electron transport system;inhibits growth of fungi - Reduction of ergosterol synthesis by inhibition of cytochrome P450 enzymes - Specificity for fungal than human cytochrome P450 enzymes

    KETOCONAZOLE ITRACONAZOLE FLUCONAZOLE VORICONAZOLE - First oral azole introduced into clinical - Available in capsule & solutions (oral & IV) - Fluorinated bistriazole - Newest triazole to enter clinical trials use - Capsule form is best absorbed in the fed state - Good water solubility & CSF penetration - Availabale in oral & IV - Increase propensity to inhibit mammalian - Oral solution is best absorbed in the fasting - Azole of choice in the treatment & - Well absorbed orally with bioavailability cytochrome P450 enzymes state secondary prophylaxis of cryptococcal >90% - Less selective for fungal P450 - Metabolized in the liver by the CYP3A4 meningitis - Low propensity to inhibit mammalian - Inhibition of mammalian P450 interferes isoenzyme system - Available in oral & IV form cytochrome P450 with biosynthesis of adrenal & gonadal - Does not affect mammalian steroid synthesis - plasma concentrations of astemizole, - Same as itraconazole in its spectrum of steroid hormones