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![Clinical uses
Narrow spectrum activity limited to
Candida, cryptococcus and Torulopsis
sp.
Use with other medicines to
↓RESISTENCE and ↑SYNERGISM
with amphotericin B for: cryptococcosis
diseminated or meningeal candidiasis
amphotericin B may ↓ renal excretion of
flucytosine → monitor plasma
[Flucytosine]
w/ intraconazole for:
IDI Students](https://image.slidesharecdn.com/idipharmacologyofantifungal1new-221110115729-667fc904/75/IDI_pharmacology_of_antifungal-1-new-ppt-24-2048.jpg)
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- 1. Pharmacology of Antifungal Agents By InternPharmacists IDI IDI Students
- 2. Spectrum of infection Superficial – no inflammatory response Mucocutaneous – confined to the superficial layers with inflammation Subcutaneous –introduced by trauma, no systemic spread Deep/systemic – more dangerous. ◦ Usually Opportunistic IDI Students
- 3. Spectrum of infection IDIStudents
- 4. Classification of ANTIFUNGAL DRUGSby chemical structure POLYENE MACROLIDES Amphotericin B, nystatin AZOLES Imidazoles: Ketoconazole, miconazole, clotrimazole Triazoles: Fluconazole, itraconazole, voriconazole. ALLYLAMINES Terbinafine, butenafine MORPHOLINE Amorolfine FLUORINATED PYRIMIDINE Flucytosine ECHINOCANDINS Caspofungin, anidulafungin, micafungin PEPTIDE-NUCLEOSIDE Nikkomycin Z TETRAHYDROFURAN DERIVATIVES Sordarins, azasordarins OTHER Griseofulvin IDI Students
- 5. Classification of ANTIFUNGALDRUGS --by mode of action Membrane disrupting agents Amphotericin B, nystatin Ergosterol synthesis inhibitors Azoles, allylamines, morpholine Nucleic acid inhibitor Flucytosine Anti-mitotic (spindle disruption) Griseofulvin Glucan synthesis inhibitors Echinocandins Chitin synthesis inhibitor Nikkomycin Protein synthesis inhibitors Sordarins, azasordarins IDI Students
- 6. MODES of ACTION IDIStudents
- 7.
- 8. Membrane disrupting agents 1)Polyenes antifungals Examples Amphotericin B, Nystatin Amphotericin A polyene antibiotic obtained from Streptomyces nodosus (1956); IDI Students
- 9. AMPHOTERICIN-B PREPARATIONS Amphotericin B ColloidalDispersion (ABCD; Amphocil™ or Amphotec™) Amphotericin B Lipid Complex (ABLC; Abelcet™) Liposomal Amphotericin B (L-AMB; Ambisome™) IDI Students
- 10. Antifungal activity ofamphotericin B VERY ACTIVE AVERAGE ACTIVITY Candida spp Criptococcus neoformans Blastomyces dermatitidis Histoplasma capsulatum Sporothrix schenckii Coccidioides immitis Paracoccidioides braziliensis Aspergillus spp Penicillium marneffei Candida lusitaniae Candida tropicalis Candida parapsilosis Scedosporium boydii Fusarium spp Malassezia furfur Trichosporon beigelii IDI Students
- 11. Mechanism of actionof polyenes It binds to fungal membrane sterols (ergosterol) creating artificial pores .This alters selective permeability to K+ and Mg2+. Resistance may develop from altered sterols or decreased sterols. IDI Students
- 12.
- 13. Clinical uses ofamphotericin B Systemic fungal infections: DOC for aspergillosis, mucormycosis, cryptococcosis, systemic sporotrichosis, and candidiasis. Co-DOC with itraconazole or fluconazole for Histoplasmosis, blastomycosis, and coccidioidomycosis Fungal meningitis (IV or intrathecal) Cryptococcus: IV w/ flucytosine Coccidioidomycosis: Intrathecally (severe and difficult to treat) Cutaneous Candida infection (TOPICAL) IDI Students
- 14. Adverse reactions Parenteral 1) Chills, fever (50%), 2) Renal damage (80%) = DOSE- DEPENDENT, REVERSIBLE ↓CREATININE Clearance; BUN MONITER KIDNEY FUNCT. + SALINE INFUSION (must give lots of fluid to decrease kidney toxicity) 3) HYPOtension, HYPOkalemia (supplement K) 4) Anemia caused by ↓ EPO by kidney IDI Students
- 15.
- 16. Polyenes—Amphotericin B Resistance ◦Development of resistance in a previously susceptible species is uncommon ◦ Mechanisms of Resistance Reductions in ergosterol biosynthesis Synthesis of alternative sterols that lessen the ability of amphotericin B to interact with the fungal membrane IDI Students
- 17. Nystatin similar toamphotericin B used topically and for GI use used against candida and dermatophytes (Epidermophyton, Trichophyton, Microsporum). IDI Students
- 18. Nucleic acid inhibitor- 3.Fluorinated pyrimidines N H N F NH2 O Flucytosine IDI Students
- 19. Mechanism of actionof Flucytosine The selective action of flucytosine is due to the failure of mammalian cells to convert flucytosine to its active metabolites. IDI Students
- 20. Mechanism of actionof Flucytosine Fungal pathogens are capable of deaminating flucytosine to 5-fluorouracil, a potent antimetabolite that is used in cancer chemotherapy). Fluorouracil is metabolized first to 5-fluorouracil-ribose monophosphate (5-FUMP) by the enzyme uracil phosphoribosyl transferase (UPRTase, also called uridine monophosphate pyrophosphorylase). As in mammalian cells, 5-FUMP then is either incorporated into RNA (via synthesis of 5-fluorouridine triphosphate) or metabolized to 5-fluoro-2'- deoxyuridine-5'-monophosphate (5-FdUMP), a potent inhibitor of thymidylate synthetase. DNA synthesis is impaired as the ultimate result of this latter reaction. IDI Students
- 21.
- 22. Flucytosine Spectrum ofActivity ◦ Active against Candida species except C. krusei Cryptococcus neoformans Aspergillus species ◦ Synergy with amphotericin B has been demonstrated The altered permeability of the fungal cell membrane produced by amphotericin allows enhanced uptake of flucytosine Mechanisms of Resistance ◦ Loss of cytosine permease that permits flucytosine to cross the fungal cell membrane ◦ Loss of any of the enzymes required to produce the active forms that interfere with DNA synthesis Resistance occurs frequently and rapidly when flucytosine is given as monotherapy IDI Students
- 23. Fungal Resistance to flucytosine The mechanism for this resistance can be loss of the permease necessary for cytosine transport or decreased activity of either UPRTase or cytosine deaminase . IDI Students
- 24. Clinical uses Narrowspectrum activity limited to Candida, cryptococcus and Torulopsis sp. Use with other medicines to ↓RESISTENCE and ↑SYNERGISM with amphotericin B for: cryptococcosis diseminated or meningeal candidiasis amphotericin B may ↓ renal excretion of flucytosine → monitor plasma [Flucytosine] w/ intraconazole for: IDI Students
- 25. Clinical uses Flucytosineis used predominantly in combination with Amphotericin B. Flucytosine is given orally at 100 mg/kg per day, in four divided doses at 6-hour intervals. Dosage must be adjusted for decreased renal function. IDI Students
- 26. 5 - FLUOROCYTOSINE ADVERSEEFFECTS • Gastrointestinal intolerance • bone marrow depression (anemia, leukopenia, thrombocytopenia) • Rash • hepatotoxicity • Headache • Confusion, hallucinations, sedation, euphoria IDI Students
- 27. Ergosterol synthesis inhibitors 1.Azoles, 2. allylamines, 3. morpholine IDI Students
- 28. Azoles There aredivided into two ; 1. Imidazoles ◦ Miconazole ◦ Clotrimazole ◦ Ketoconazole 2.Triazoles ◦ Itraconazole ◦ Fluconazole ◦ Voriconazole IDI Students
- 29.
- 30. Mechanism of Actionof Azoles inhibit the synthesis of ergosterol by blocking demethylation (14-demethylase) of lanosterol to ergosterol - also inhibit cytochrome P450 activity. IDI Students
- 31. Triazoles—Spectrum of Activity FluconazoleItraconazole Voriconazole Posaconazole C. albicans +++ ++ +++ +++ C. glabrata + + ++ ++ C. krusei -- + +++ ++ C. tropicalis +++ ++ +++ +++ C. parapsilosis +++ ++ +++ +++ C. lusitanae ++ ++ +++ +++ Aspergillus -- ++ +++ +++ Cryptococcus +++ +++ +++ +++ Coccidioides +++ +++ +++ +++ Blastomyces ++ +++ ++ +++ Histoplasma + +++ ++ +++ Fusarium -- -- ++ ++ Scedosporium -- +/- + +/- Zygomycetes - - - ++ IDI Students
- 32. Azole derivatives • FIRSTGENERATION – Ketoconazole • SECOND GENERATION – Fluconazole – Itraconazole • THIRD GENERATION – Voriconazole – Ravuconazole (BMS-207147) – Posaconazole R-120758 SYN-2869 T-8581 VR-9746 VR-9751 (D0870) IDI Students
- 33. MOST COMMON INDICATIONS TineaInfections (1-4 wks) Ketoconazole Terbinafine Onychomycosis (6wks-1yr) Itraconazole Terbinafine Vaginal Candidiasis (1d- 2wks) Fluconazole Nystatin Oropharyngeal Candidiasis (7-14d) o Fluconazole o Itraconazole o Nystatin Esophageal Candidiasis (14-21d) o Fluconazole o Itraconazole o Voriconazole Systemic Infections Fluconazole Voriconazole IDI Students
- 34. Triazoles—Fluconazole Dose ◦ 100to 400 mg daily ◦ Renal impairment: CrCl >50 ml/min, give full dose CrCl<50 ml/min, give 50% of dose Dialysis: replace full dose after each session Drug Interactions ◦ Minor inhibitor of CYP 3A4 ◦ Moderate inhibitor of CYP 2C9 Warfarin, phenytoin, cyclosporine, tacrolimus, rifampin/rifabutin, sulfonylureas Adverse Drug Reactions ◦ Well tolerated ◦ Nausea ◦ Elevated LFTs UNC Hospital Formulary IDI Students
- 35. Triazoles—Itraconazole Dose ◦ 200to 400 mg/day (capsules) Drug Interactions ◦ Major substrate of CYP 3A4 ◦ Strong inhibitor of CYP 3A4 ◦ Many Drug Interactions Adverse Drug Reactions ◦ Contraindicated in patients with CHF due to negative inotropic effects ◦ QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest in the setting of drug interactions ◦ Hepatotoxicity ◦ Rash ◦ Hypokalemia ◦ Nausea and vomiting IDI Students
- 36. Ergosterol synthesis inhibitors 2) ALLYLAMINES 1. Terbinafine, 2. butenafine IDI Students
- 37. Terbinafine Mechanism ofaction Inhibits squalene 2, 3- epoxidase. Squalene is cidal to sensitive organisms. Clinical uses Used orally for dermatophytes Adverse effects include hepatitis and rashes. Both are rare. IDI Students
- 38.
- 39. Amorolfine Inhibits ergosterol synthesis byinhibiting sterol reductase enzyme Clinical uses In tinea infections only For topical use as nail lacquer. IDI Students
- 40.
- 41. Griseofulvin Mechanism of action binds to microtubules comprising the spindles and inhibits mitosis. Uses Tinea infections of the nails and hair incorporates into keratin and protects newly formed skin. fungistatic IDI Students
- 42.
- 43. Untoward effects nausea,headache hepatoxicity renal toxicity photosensitivity can precipitate acute intermittent porphyria possibly teratogenic induces metabolism of some other drugs hypersensitivity IDI Students
- 44. Glucan synthesis inhibitors Echinocandins 1. Caspofungin 2. anidulafungin 3. micafungin IDI Students
- 45. The Fungal CellWall mannoproteins b1,6 glucans b1,3 chitin ergosterol b1,3 glucan synthase Cell membrane Atlas of fungal Infections, Richard Diamond Ed. 1999 Introduction to Medical Mycology. Merck and Co. 2001 IDI Students
- 46. Mechanism of action Inhibits 1,3-b-D-glucan synthase, which is required for glucan polymerization in the wall of certain fungi IDI Students
- 47. Echinocandins—Spectrum of Activity Gallagher JC,et al. Expert Rev Anti-Infect Ther 2004;2:253-268 Candida Aspergillus Cryptococcus Coccidioides Blastomyces Histoplasma Fusarium Scedosporidium Zygomycetes albicans glabrata krusei tropicalis parapsilosis lusitanae guilliermondii +++ +++ +++ +++ + +++ + +++ -- ++ ++ -- - - - IDI Students
- 48. Echinocandins—Adverse Effects Generally welltolerated Phlebitis, GI side effects, Hypokalemia Abnormal liver function tests Caspofungin ◦ Tends to have higher frequency of liver related laboratory abnormalities ◦ Higher frequency of infusion related pain and phlebitis IDI Students
- 49. Thanks for Listening IDIStudents