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 - Reduced bioavailability when taken with cissapride, cyclosporine, rifampin, action - Interaction with P450 enzymes can alter rifamycins rifabutin, sulfonylureas, theophylline & - Good activity against candida species the metabolism of other drugs leading to - Azole of choice for dimorphic fungi warfarin - fluconazole-resistant species such as C. enhanced toxicity histoplasma, blastomyces, sporothrix krusei, dimorphic fungi, pathogenic - Reaches the keratinocytes efficiently - Oral solution is effective for use in molds including aspergillus - Concentration in vaginal fluids is oropharyngeal & esophageal candidiasis approaches that in plasma - Onychomycosis can be treated with either 200 mg OD X 12 wks or as 200 mg BID X 1 wk out of each month SYSTEMIC ANTIFUNGAL DRUGS FOR MUCOCUTANEOUS INFECTIONS GRISEOFULVIN PHARMACOKINETICS: MECHANISM OF ACTION: THERAPEUTIC USES: ADVERSE REACTIONS: - Practically insoluble in water - Production of multinucleate cells as`the - Mycotic disease of the skin, hair & nails - Allergic syndrome - Fungistatic in vitro for dermatophytes drug inhibits fungal mitosis due to Microsporum, Trichophyton, or - hepatitis microsporum, epidermophytom & - Causes disruption of the mitotic spindle Epidermophyton



PHARMACOKINETICS: MECHANISM OF ACTION: THERAPEUTIC USES: ADVERSE REACTIONS: trichophyton by interacting with polymerized - Tinea capitis (M. canis) - No effect on bacteria & other fungi microtubules - Ringworm of the glabrous skin - Deposited in the newly forming skin - Tinea corporis, cruris (T. rubrum, T. where it binds to keratin mentagrophytes) - Administered 2-6 wks for skin & hair - Hyperlkeratosis (T. rubrum) infections TERBINAFINE - Synthetic allylamine - Available in oral formulation - Used in the treatment of dermatophytoses especially onychomycosis - Keratophillic, fungicidal - Inhibits the enzyme SQUALENE EPOXIDASE - Leads to the accumulation of the sterol squalene - OD X12 wks achieves 90% cure rate for onychomycosis TOPICAL ANTIFUNGAL AGENTS - Superficial fungal infections confined to the striatum corneum, squamous mucosa or cornea - Ringworm, candidiasis, tinea versicolor, tinea nigra, fungal keratitis - Not successful for mycoses of the nails & hair - No place for the treatment of subcutaneous mycosis POLYENE ANTIFUNGAL AGENTS NYSTATIN AMPHOTERICIN B - Polyene macrolide - Topical form (Fungizone) - Structurally similar to Amphotericin B - Cutaneous & mucocutaneous candidiasis - Toxic for parenteral administration - Lotion, ointment & cream - Available in creams, ointments, suppositories - Oropharyngeal thrush, vaginal candidiasis, intertriginous candidal infections IMIDAZOLE & TRIAZOLE FOR TOPICAL USE: CLOTRIMAZOLE MICONAZOLE CICLOPIROXAMINE HALOPROGIN NAFTIFENE - Available as 1% cream, lotion, - Readily penetrates the striatum - Broad spectrum - Halogenated phenolic ether - Inhibit squalene-2,3- epoxidase & solution corneum of the skin - Fungicidal to C. albicans, E. - Fungicidal to various species of - Inhibits biosynthesis of - 1% or 2% vaginal cream or - Persists for >4 days after flocosum, M. canis, T. Epidermophyton, ergosterol vaginal tablets application mentagrophytes, T. rubrum Pityrosporum, Microsporum, - Fungicidal activity - Skin applications BID - Safe for use during pregnancy - Inhibits the growth of Trichophyton & Candida - 1% cream or gel - Vaginal applications 100 mg for vaginal use Malassezia furfur - Poorly absorbed through the - Topical treatment of tinea tab OD at bedtime X 7 days or - Ointment, cream, solution, - Penetrates the dermis skin cruris & tinea corporis 200 mg OD X 3 days spray, powder or lotion - Converted to thrichlorophenol - Cutaneous candidiasis & tinea - Vaginal cream, suppositories in the body versicolor - Tinea pedis, tinea cruris, & - Cream or solution BID X 2-4 tinea versicolor wks - Principal use for tinea pedis - Tinea cruris, tinea versicolor, tinea corporis DRUG ACTION CLINICAL USE UNDESIRABLE EFFECTS PHARMACOKINETICS NOTES Disrupts plasma membrane of DOC: systemic fungal infections, Poor therapeutic index (toxic at Slow IV for systemic infections; CBC, urinalysis, liver enzymes, Amphotericin B



DRUG ACTION CLINICAL USE UNDESIRABLE EFFECTS PHARMACOKINETICS NOTES fungal cells, greater affinity for fungal meningitis & fungal therapeutic dose). Fever & chills, intrathecal for meningitis, bladder BUN, Crea, & electrolytes should ergosterol urinary tract infections nephrotoxicity, nausea, headache, irrigation for cystitis. No need to be checked before and during tx thrombophlebitis, anemia, reduce dose with renal hepatotoxicity, cardiotoxicity dysfunction. DOC: Intestinal candidiasis or oral Few adverse effects PO. Negligible absorption, fecal Nystatin thrush excretion Impairs synthesis pf ergosterol DOC: P. brasiliensis, thrush, Nausea, diarrhea, headaches, rsh, PO. Acid pH required for Follow LFTs. Stop during signs of Ketoconazole chronic mucocutaneous dizziness, fatal hepatic necrosis, dissolution. Absorption decreased liver abnormalities candidiasis, dermatophytes gynecomastia. by food, antacids, cimetidine Risk of cardiac arrhythmia with Terfenadine Inhibits fungal cytochrome P450. Systemic histoplasmosis, Nausea, headache, rash, vomiting, PO/IV. Long half life. Excellent No effect on testosterone Fluconazole Damages plasma membrane by blastomycosis, coccidiomycosis or diarrhea penetration of CSF, eye, urine. synthesis. inhibiting sterol demethylation sporotrichosis. Opportunistic Hepatic metabolism cryptococcosis, candidiasis, candidal thrush, vaginitis, esophagitis Aspergillosis, histoplasmosis, Nausea, edema, hepatitis. No PO. Requires acidic environment No effect on testosterone synthesis Itraconazole coccidiomycosis, sporotrichosis, gynecomastia or breast pain. Risk for absorption paracoccidiomycosis, tinea or of fatal cardiac arrhythmias w/ candidal infections terfenadine unknown DOC: candida dermatophyte topical Clotrimazole infections of the skin Vaginal candidiasis, severe Phlebitis, pruritus, nausea, fever, Vaginal suppositories/ topical/IV Miconazole systemic fungal infections rash, vomiting Deaminated to 5-FU by the Leucopenia, nausea, diarrhea, Inc Easily penetrates CNS. Renal Fungal resistance develops Flucytosine fungus. Incorporated into RNA. LFTs, bone marrow depression excretion Metabolized to 5-FdURD w/c inhibits thymidilate synthetase Interferes w/ synthesis & Dermatophytes of hair, skin, & Headaches, GI upset, dec memory PO. Water insoluble, powder Contraindicated w/ pregnant Griseofulvin polymerization of nucleic acids nails. Up to 6 months tx may be & judgement, leucopenia, absorbed fairly well, women. Drug binds to keratin of required teratogenic administration w/ fatty meal aids growing tissues absorption Inhibits squalene epoxidase that Toenail infection due to Neutropenia, skin infections, PO. Long half life. Good tissue Monitor blood counts Terbinafine converts squalene to ergosterol in trichophyton species ophthalmic toxicity penetration fungi MISCELLANEOUS ANTIFUNGAL AGENTS UNDECYCLENIC ACID BENZOIC ACID & SALICYLIC ACID PROPIONIC ACID & CAPRYLIC ACID POTASSIUM IODIDE - Yellow liquid with a characteristic rancid - Whitfield’s ointment - Treatment of dermatomycoses - Treatment of mucocutaneous odor - Combines fungistatic activity of benzoic - Low efficacy sporotrichosis - Fungistatic, fungicidal w/ prolonged use acid w/ keratolytic action of salicylic acid - Foam, ointment, cream, powder, spray - Mainly for the treatment of tinea pedis powder, soap & liquid - Eradication occurs after the infectd - Ringworm, tinea pedis stratum corneum is shed - Salicylate accelerates the desquamation


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