Antifungal agents

6,242 views

Published on

0 Comments
11 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
6,242
On SlideShare
0
From Embeds
0
Number of Embeds
29
Actions
Shares
0
Downloads
321
Comments
0
Likes
11
Embeds 0
No embeds

No notes for slide

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>www.freelivedoctor.com
  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. www.freelivedoctor.com
  25. 25. Model for Amphotericin B induced Pore in Cell Membrane In fungi: ergosterol in membranes: higher affinity than mammalian cholesterol for AmB www.freelivedoctor.com
  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>www.freelivedoctor.com
  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 www.freelivedoctor.com
  28. 28. Influence of Amphotericin B on intracellular Ca ++ levels in glomerular mesangial cells Theory Pore ↑ Na entry Depolarization Voltage-dep. Ca channels Contraction www.freelivedoctor.com
  29. 29. Calcium channel blockers are protective against AmB- nephrotoxicity in-vivo in rats Salt loading is protective against nephrotoxicity in vivo in animals www.freelivedoctor.com
  30. 30. Salt loading or Supplements Protect Against AmB- Nephrotoxicity In Humans www.freelivedoctor.com
  31. 31. Alternative Formulations to Decrease Toxicity www.freelivedoctor.com
  32. 32. Lipid formulations: 20-50 times more expensive than AmB-deoxycholate www.freelivedoctor.com
  33. 33. Renal Effects of AmB-DOC & Liposomal AmB www.freelivedoctor.com
  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 www.freelivedoctor.com
  35. 35. www.freelivedoctor.com
  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>www.freelivedoctor.com
  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>www.freelivedoctor.com
  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>www.freelivedoctor.com
  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>www.freelivedoctor.com
  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>www.freelivedoctor.com

×