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  1. An Introduction to Anti-fungal Pharmacology The following slides were generously supplied by ProfessorRussell E. Lewis, Pharm.D., BCPS University of Houston College of Pharmacy, University of Texas M.D. Anderson Cancer Center. With lecture notes written by Hannah Woodcock and Jenny Bartholomew, University of Manchester, UK.

  2. Types of fungal infections - Mycoses • Superficial mycoses • Affect the skin, hair and nails • Subcutaneous mycoses (tropical) • Affect the muscle and connective tissue immediately below the skin • Systemic (invasive) mycoses • Involve the internal organs • Primary vs. opportunistic • Allergic mycoses • Affect lungs or sinuses • Patients may have chronic asthma, cystic fibrosis or sinusitis There is some overlap between these groups

  3. What are the targets for antifungal therapy? Cell membrane Fungi use principally ergosterol instead of cholesterol DNA Synthesis Some compounds may be selectively activated by fungi, arresting DNA synthesis. Cell Wall Unlike mammalian cells, fungi have a cell wall Atlas of fungal Infections, Richard Diamond Ed. 1999 Introduction to Medical Mycology. Merck and Co. 2001

  4. Cell Membrane Active Antifungals Cell membrane • Polyene antibiotics - Amphotericin B, lipid formulations - Nystatin (topical) • Azole antifungals - Ketoconazole - Itraconazole - Fluconazole - Voriconazole - Miconazole, clotrimazole (and other topicals)

  5. Azole Antifungals for Systemic Infections Imidazole • Ketoconazole (Nizoril) • Itraconazole (Sporanox) • Fluconazole (Diflucan) • Voriconazole (Vfend) Triazoles “2nd generationtriazole” Fluconazole Ketoconazole

  6. Azoles - Mechanism • In fungi, the cytochrome P450-enzyme lanosterol 14-a demethylase is responsible for the conversion of lanosterol to ergosterol • Azoles bind to lanosterol 14a-demethylase inhibiting the production of ergosterol • Some cross-reactivity is seen with mammalian cytochrome p450 enzymes • Drug Interactions • Impairment of steroidneogenesis (ketoconazole, itraconazole)

  7. Effect of azoles on C. albicans Before exposure After exposure

  8. Azoles - Pharmacodynamics • Concentration-independent fungistatic agents • Dosage escalation may be necessary when faced with more resistant fungal species (e.g. Candida glabrata) • Goal of dosing is to maintain AUC:MIC >50 • i.e. maintain concentrations 1-2xMIC for the entire dosing interval

  9. Ketoconazole • Spectrum: yeasts and moulds - poor absorption limits its role for severe infections, generally used in mucosal infections only • Pharmacokinetics • Variable oral absorption, dependent on pH (often given with cola or fruit juice) • T1/2 7-10 hours • Protein binding > 99% • Hepatic, bile and kidney elimination

  10. Ketoconazole - Adverse effects • Adverse effects • N&V, worse with higher doses (800 mg/day) • Hepatoxicity (2-8%), increase in transaminases, hepatitis • Dose related inhibition of CYP P450 responsible for testosterone synthesis • Gynecomastia, oligosperma, decreased libido • Dose-related inhibition of CYP P450 responsible for adrenal cortisol synthesis

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