Antifungal agents


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Antifungal agents

  1. 1. Antifungal Agents
  2. 2. Antifungal Agents <ul><li>Drugs used to treat infections caused by fungi </li></ul><ul><li>Systemic and topical </li></ul>
  3. 3. Fungi <ul><li>Also known as mycoses </li></ul><ul><li>Very large and diverse group of microorganisms </li></ul><ul><li>Broken down into yeasts and molds </li></ul>
  4. 4. Yeasts <ul><li>Single-cell fungi </li></ul><ul><li>Reproduce by budding </li></ul><ul><li>Very useful organisms </li></ul><ul><ul><li>Baking </li></ul></ul><ul><ul><li>Alcoholic beverages </li></ul></ul>
  5. 5. Molds <ul><li>Multicellular </li></ul><ul><li>Characterized by long, branching filaments called hyphae </li></ul>
  6. 6. Mycotic Infections <ul><li>Four General Types </li></ul><ul><li>Cutaneous </li></ul><ul><li>Subcutaneous </li></ul><ul><li>Superficial </li></ul><ul><li>Systemic* </li></ul><ul><ul><li>*Can be life-threatening </li></ul></ul><ul><ul><li>*Usually occur in immunocompromised host </li></ul></ul>
  7. 7. Mycotic Infections <ul><li>Candida albicans </li></ul><ul><li>Due to antibiotic therapy, antineoplastics, or immunosuppressants </li></ul><ul><li>May result in overgrowth and systemic infections </li></ul>
  8. 8. Mycotic Infections <ul><li>In the mouth: </li></ul><ul><li>Oral candidiasis or thrush </li></ul><ul><li>Newborn infants and immunocompromised patients </li></ul>
  9. 9. Mycotic Infections <ul><li>Vaginal candidiasis: </li></ul><ul><li>“ Yeast infection” </li></ul><ul><li>Pregnancy, diabetes mellitus, oral contraceptives </li></ul>
  10. 10. Antifungal Agents <ul><li>Systemic </li></ul><ul><li>Examples: amphotericin B, fluconazole, ketoconazole, itraconazole </li></ul><ul><li>Topical </li></ul><ul><li>Examples: clotrimazole, miconazole, nystatin </li></ul>
  11. 11. Antifungal Agents <ul><li>Broken down into four major groups based on their chemical structure </li></ul><ul><li>Polyenes: amphotericin B and nystatin </li></ul><ul><li>Flucytosine </li></ul><ul><li>Imidazoles: ketoconazole, miconazole, clotrimazole, fluconazole </li></ul><ul><li>Griseofulvin </li></ul>
  12. 12. Antifungal Agents: Mechanism of Action <ul><li>Polyenes: amphotericin B and nystatin </li></ul><ul><li>Bind to sterols in cell membrane lining </li></ul><ul><li>Allow K+ & Mg++ to leak out, altering fungal cell metabolism </li></ul><ul><li>Result: fungal cell death </li></ul>
  13. 13. Antifungal Agents: Mechanism of Action <ul><li>flucytosine </li></ul><ul><li>Also known as 5-fluorocytosine (antimetabolite) </li></ul><ul><li>Taken up by fungal cells and interferes with DNA synthesis </li></ul><ul><li>Result: fungal cell death </li></ul>
  14. 14. Antifungal Agents: Mechanism of Action <ul><li>Imidazoles ketoconazole, miconazole, clotrimazole, fluconazole </li></ul><ul><li>Inhibit an enzyme, resulting in cell membrane leaking </li></ul><ul><li>Lead to altered cell membrane </li></ul><ul><li>Result: fungal cell death </li></ul>
  15. 15. Antifungal Agents: Mechanism of Action <ul><li>griseofulvin </li></ul><ul><li>Disrupts cell division </li></ul><ul><li>Result: inhibited fungal mitosis (reproduction) </li></ul>
  16. 16. Antifungal Agents: Side Effects <ul><li>amphotericin B “Shake and Bake” </li></ul><ul><li>fever chills headache anorexia </li></ul><ul><li>malaise nausea hypotension tachycardia </li></ul><ul><li>muscle and joint pain </li></ul><ul><li>lowered potassium and magnesium levels </li></ul><ul><li>*renal toxicity </li></ul><ul><li>*neurotoxicity: seizures and paresthesias </li></ul>
  17. 17. Antifungal Agents: Side Effects <ul><li>fluconazole </li></ul><ul><li>nausea, vomiting, diarrhea, abdominal pain, </li></ul><ul><li>increased liver function studies </li></ul><ul><li>flucytosine </li></ul><ul><li>nausea, vomiting, anorexia </li></ul><ul><li>griseofulvin </li></ul><ul><li>rash, urticaria, headache, nausea, vomiting, anorexia </li></ul>
  18. 18. Antifungal Agents: Nursing Implications <ul><li>Before beginning therapy, assess for hypersensitivity, possible contraindications, and conditions that require cautious use. </li></ul><ul><li>Obtain baseline VS, CBC, liver function studies, and ECG. </li></ul><ul><li>Assess for other medications used (prescribed and OTC) in order to avoid drug interactions. </li></ul>
  19. 19. Antifungal Agents: Nursing Implications <ul><li>Follow manufacturer’s directions carefully for reconstitution and administration. </li></ul><ul><li>Monitor VS of patients receiving IV infusions every 15 to 30 minutes. </li></ul><ul><li>During IV infusions, monitor I & O and urinalysis findings to identify adverse renal effects. </li></ul>
  20. 20. Antifungal Agents: Nursing Implications <ul><li>amphotericin B </li></ul><ul><li>To reduce the severity of the infusion-related reactions, pretreatment with an antipyretic (acetaminophen), antihistamines, and antiemetics may be given. </li></ul><ul><li>A test dose of 1 mg per 20 mL 5% dextrose in water infused over 30 minutes should be given. </li></ul><ul><li>Use IV infusion pumps and the most distal veins possible. </li></ul>
  21. 21. Antifungal Agents: Nursing Implications <ul><li>Tissue extravasation of fluconazole at the IV site may lead to tissue necrosis—monitor IV site carefully. </li></ul><ul><li>Oral forms of griseofulvin should be given with meals to decrease GI upset. </li></ul><ul><li>Monitor carefully for side/adverse effects. </li></ul>
  22. 22. Antifungal Agents: Nursing Implications <ul><li>Monitor for therapeutic effects: </li></ul><ul><li>Easing of the symptoms of infection </li></ul><ul><li>Improved energy levels </li></ul><ul><li>Normal vital signs, including temperature </li></ul>
  23. 23. Antifungal Drugs <ul><li>Polyene antibiotics: Amphotericin B, nystatin </li></ul><ul><li>Antimetabolites: 5-Fluorocytosine </li></ul><ul><li>Azoles: </li></ul><ul><li>Imidazoles: Ketoconazole, miconazole (topical) </li></ul><ul><li>Trizoles: Itraconazole, Fluconazole </li></ul><ul><li>Griseofulvin </li></ul><ul><li>Topical antifungal agents: imidazoles, polyenes and others. </li></ul>
  24. 24. Drug of Choice for most systemic fungal infections. Even those susceptible to others but where the disease rapidly progressive, in Immunocompromized or involves CNS.
  25. 25. Model for Amphotericin B induced Pore in Cell Membrane In fungi: ergosterol in membranes: higher affinity than mammalian cholesterol for AmB
  26. 26. Adverse Effects <ul><li>Acute: Infusion-related </li></ul><ul><ul><li>Chills, fever, dyspnea, nausea, vomiting, bronchospasm, hypotension, convulsions </li></ul></ul><ul><li>Chronic </li></ul><ul><ul><li>Nephrotoxicity </li></ul></ul><ul><ul><li>azotemia, impaired concentration, impaired urinary acidification, K & Mg wasting with hypokalemia and hypomagnesemia </li></ul></ul><ul><ul><li>Normochromic, normocytic anemia </li></ul></ul><ul><ul><li>(↓ erythropoietin) </li></ul></ul>
  27. 27. Q A SNGFR R E R A P GC ΔP P T K f Influence of Amphotericin B Infusion on Determinants of Single Nephron GFR
  28. 28. Influence of Amphotericin B on intracellular Ca ++ levels in glomerular mesangial cells Theory Pore ↑ Na entry Depolarization Voltage-dep. Ca channels Contraction
  29. 29. Calcium channel blockers are protective against AmB- nephrotoxicity in-vivo in rats Salt loading is protective against nephrotoxicity in vivo in animals
  30. 30. Salt loading or Supplements Protect Against AmB- Nephrotoxicity In Humans
  31. 31. Alternative Formulations to Decrease Toxicity
  32. 32. Lipid formulations: 20-50 times more expensive than AmB-deoxycholate
  33. 33. Renal Effects of AmB-DOC & Liposomal AmB
  34. 34. f-AmB L-AmB f-AmB L-AmB AmB-DOC Differential Effects of L-AmB on Mammalian and Fungal Cells, in Contrast to free AmB RBC Fungal Cell
  35. 35.
  36. 36. 5-Fluorocytosine A fluorinated pyrimidine <ul><li>Converted to 5 fluorouracil by a deaminase then to 5-fdUMP, which inhibits thymidylate synthase and DNA synthesis </li></ul><ul><li>Selective toxicity to fungal cells (no deaminase in mammalian cells) </li></ul><ul><li>Resistance is common. Do not use alone, but in combination with AmB cryptococcal meningitis </li></ul><ul><li>Bone marrow toxicity – pancytopenia -reversible </li></ul>
  37. 37. The Azoles Imidazoles and Triazoles <ul><li>Triazoles newer with fewer side effects </li></ul><ul><li>Impair synthesis of ergosterol; inhibit sterol 14 α-demethylase (of cyt. P450). Acumulation of precursors which inhibit growth. </li></ul><ul><li>Mammalian cells can incorporate already formed cholesterol; fungi have to synthesize </li></ul><ul><li>Adverse effects due to inhibition of mammalian steroid synthesis </li></ul><ul><li>Drug interactions due to inbibition of cyt. P450 enzymes. </li></ul>
  38. 38. Ketoconazole (older, more toxic, replaced by itraconazole, but less costly) <ul><li>Absorption variable (better in acidic medium) </li></ul><ul><li>Poor concentration in CSF </li></ul><ul><li>Metabolized by Cyt. P450 enzymes </li></ul><ul><li>Adverse effects: </li></ul><ul><li>- Nausea, anorexia, vomiting </li></ul><ul><li>- Endocrine: menstrual abnormalities, gynecomastia, azoospermia, decreased libido and potency </li></ul><ul><li>- Hypertension and fluid retention </li></ul><ul><li>- Hepatitis (rare-fatal) </li></ul><ul><li>- Drug Interactions (inhibition of cyt. P450) </li></ul><ul><li>Therapeutic Use: coccidiomycosis, histoplasmosis if not severely ill or immunocompromized. Oral, esophageal, mucocutaneous candidiasis </li></ul>
  39. 39. Triazoles <ul><li>Itraconazole </li></ul><ul><li>Varied absorption. Metabolized by cyt P450 </li></ul><ul><li>Has less endocrine effects but occur at high doses </li></ul><ul><li>Less hepatitis </li></ul><ul><li>Histoplasmosis and blastomycosis </li></ul><ul><li>Many drug interactions (due to inhibition of cyt P4503A4) </li></ul><ul><li>Fluconazole </li></ul><ul><li>Completely absorbed and better tolerated </li></ul><ul><li>Renal excretion </li></ul><ul><li>Less endocrine effects </li></ul><ul><li>Penetrates well into CSF </li></ul><ul><li>Cryptococcal, coccidial meningitis. Candidiasis. </li></ul><ul><li>Drug Interactions </li></ul>
  40. 40. Other Antifungal Agents <ul><li>Griseofulvin </li></ul><ul><li>Binds to microtubules/ disrupts mitosis </li></ul><ul><li>Deposits in keratin layers </li></ul><ul><li>Dermatophytes actively concentrate it </li></ul><ul><li>Infections of skin, hair, nails; Prolonged therapy . </li></ul><ul><li>Toxicity: headache, neuro & hepatotoxicity, photo-sensitivity, carcinogenic. </li></ul><ul><li>Topical Antifungals </li></ul><ul><li>For stratum corneum, mucosa, cornea by dermatophytes & Candida. </li></ul><ul><li>Not for subcutaneous, nail or hair infections. </li></ul><ul><li>Many azoles; Tolnaftate; nystatin (Candida only); naftifine; terbinafine; Whitfield’s ointment (Benzoic+Salicylic Acid). </li></ul>