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Antifungals

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Department of Pharmacology, Lahore Medical & Dental College

Publié dans : Santé & Médecine, Technologie
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Antifungals

  1. 1. Antifungal Agents Dr. Salman Iftikhar Pharmacology
  2. 3. <ul><li>Mechanisms </li></ul><ul><ul><li>Interact with ergosterol in fungal membranes to form artificial &quot;pores,&quot; which disrupt membrane permeability. </li></ul></ul><ul><ul><li>Resistant fungal strains appear to have low ergosterol content in their cell membranes. </li></ul></ul>POLYENES (AMPMOTERICIN B [AMP B], NYSTATIN)
  3. 4. Activity and Clinical Uses <ul><li>Amp B has a wide fungicidal spectrum and remains the DOC (or co-DOC) for severe infections caused by Aspergillus, Candida, Cryptococcus, Histoplasma, Mucor, and Sporothrix. </li></ul><ul><li>Amp B is synergistic with flucytosine in candidiasis and cryptococcoses. </li></ul><ul><li>Nystatin (too toxic for systemic use) is used topically for localized infections (e.g., candidiasis). </li></ul>
  4. 5. <ul><li>Biodisposition </li></ul><ul><ul><li>Amp R is given by slow IV infusion-poor penetration into the CNS (intrathecal possible). </li></ul></ul><ul><ul><li>Clearance is slow (half-life >2 weeks), via both metabolism and renal elimination. </li></ul></ul>
  5. 6. <ul><li>Adverse Effects </li></ul><ul><ul><li>Infusion-Related </li></ul></ul><ul><ul><li>Fever, chills, muscle rigor, hypotension (histamine release) occur during IV infusion (a test dose </li></ul></ul><ul><ul><li>is advisable) and can be alleviated partly by pretreatment with NSAIDs, antihistamines, meperidine, </li></ul></ul><ul><ul><li>and adrenal steroids. </li></ul></ul><ul><li>Dose-Dependent </li></ul><ul><ul><li>Nephrotoxicity includes  GFR, tubular acidosis,  K + and Mg 2+ , and anemia through  erythropoietin </li></ul></ul>
  6. 7. AZOLES (KETOCONAZOLEI FLUCONAZOLEI ITRACONAZOLE) <ul><li>Mechanism </li></ul><ul><ul><li>Fungicidal and interfere with the synthesis of ergosterol by inhibiting the P450-dependent 14 alpha-demethylation which converts lanosterol to ergosterol. </li></ul></ul><ul><ul><li>Resistance occurs via decreased intracellular accumulation of azoles. </li></ul></ul>
  7. 8. <ul><li>Ketoconazole </li></ul><ul><ul><li>Co-DOC for Paracoccidioides and backup for Blastomyces and Histoplasma. </li></ul></ul><ul><ul><li>Oral use in mucocutaneous candidiasis or dermatophytoses. </li></ul></ul><ul><ul><li>Not distributed to CNS </li></ul></ul><ul><li>Fluconazole </li></ul><ul><ul><li>DOC for esophageal and invasive candidiasis and coccidioidomycoses. </li></ul></ul><ul><ul><li>Prophylaxis and suppression in cryptococcal meningitis. </li></ul></ul>
  8. 9. <ul><li>ltraconazole </li></ul><ul><ul><li>DOC in blastomycoses and sporotrichoses </li></ul></ul><ul><li>Clotrimazole and Miconazole </li></ul><ul><ul><li>Used topically for candidal and dermatophytic infections </li></ul></ul><ul><li>Biodisposition </li></ul><ul><ul><li>Class: effective orally. </li></ul></ul><ul><ul><li>Absorption of ketoconazole is decreased by antacids. </li></ul></ul><ul><ul><li>Absorption of itraconazole is increased by food. </li></ul></ul><ul><ul><li>Only fluconazole penetrates into the CSF and can be used in meningeal infection. Fluconazole </li></ul></ul><ul><ul><li>is eliminated in the urine, largely in unchanged form. </li></ul></ul><ul><ul><li>Ketoconazole and itraconazole are metabolized by liver enzymes. </li></ul></ul>
  9. 10. <ul><li>Adverse Effects </li></ul><ul><ul><li>Decreased synthesis of steroids, including cortisol and androgens ->  libido, gynecomastia, </li></ul></ul><ul><ul><li>menstrual irregularities </li></ul></ul><ul><ul><li>Rash </li></ul></ul><ul><ul><li>Fluid retention ->↑ BP </li></ul></ul><ul><ul><li>LFTs and rare hepatotoxicity </li></ul></ul><ul><ul><li>Inhibition of hepatic P450s ->  metabolism of cyclosporine, phenytoin, warfarin, etc. </li></ul></ul><ul><ul><li>Disulfiram-like reactions with ethanol </li></ul></ul>
  10. 11. OTHER ANTIFUNGALS <ul><li>Flucytosine </li></ul><ul><ul><li>Activated by fungal cytosine deaminase to 5-fluorouracil (5-FU), which after triphosphorylation is incorporated into fungal RNA. </li></ul></ul><ul><ul><li>5-FU also forms 5-fluorodeoxyuridine monophosphate (5-Fd-UMP), which inhibits thymidylate synthase ->  thymine. </li></ul></ul><ul><ul><li>Resistance emerges rapidly if flucytosine is used alone. </li></ul></ul><ul><ul><li>Use in combination with amp B in severe candidal and cryptococcal infections-enters CSF. </li></ul></ul><ul><ul><li>Toxic to bone marrow </li></ul></ul>
  11. 12. Griseofulvin <ul><li>Active only against dermatophytes (orally, not topically) by depositing in newly formed keratin and disrupting microtubule structure. </li></ul><ul><li>Adverse effects: </li></ul><ul><ul><li>headache, thrush, peripheral neuritis, phototoxicity, potentiates ethanol-avoid with history of porphyria. </li></ul></ul>
  12. 13. Terbinafine <ul><li>Active only against dermatophytes by inhibiting squalene epoxidase ->  ergosterol. </li></ul><ul><li>Possibly superior to griseofulvin in onychomycoses. </li></ul><ul><li>Adverse effects: </li></ul><ul><ul><li>GI distress, rash, headache, ↑ liver function tests (LFTs) -> possible hepatotoxicity </li></ul></ul>

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