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anti fungal.pdf

  1. Antifungal Drugs D. Kumaraswamy Department of pharmacology SRM MCH&RC
  2. FUNGAL INFECTIONS (MYCOSES) Superficial Deep/ systemic
  3. Fungal infections (Superficial) z Dermatomycosis (bcc cup) z Tinea pedis (athlete’s foot) z Tinea corporis (skin ringworm) z Tinea cruris (groin) z Tinea capitis (scalp) z Tinea unguium (nails) z Tinea barbae (beard) z Tinea mannum(hand) z Candidiasis – skin, mouth, vagina oropharynx
  4. DEEP MYCOSES Blastomyces Candida Coccidiodes Cryptococcus Histoplasma aspergilus
  5. Antifungal drugs- Classification (5) 1. ANTIBIOTICS Amphotericin B, (AMB), Nystatin, Hamcyin, Natamycin Griseofulvin 2. ANTIMETABOLITES: 5-Fluorocytosine (5-FC) inhibition of nucleic acid synthesis
  6. Antifungal drugs- Classification 3. AZOLES z Imidazoles: (Topical): Clotrimazole, Econazole, Miconazole, Oxiconazole (Systemic): Ketoconazole Trizoles: ( Systemic) Itraconazole, Fluconazole, Voriconazole Inhibition of ergosterol synthesis 4. ALLYLAMINE: Terbinafine Inhibition of lanosterol and ergosterol synthesis 5. OTHER TOPICAL AGENTS: Tolnaftate, Undecylenic acid, Benzoic acid, Quiniodochlor, Ciclopirox olamine, Sod. thiosulfate.
  7. Amphotericin B - MOA z In fungi: ergosterol in membranes: higher affinity than mammalian cholesterol for AmB z Ergosterol: Only present in fungal cell membrane and not in animal cell z Ergosterol: Polyenes combine with it, get inserted into the membrane and several molecules together orient themselves and form a micropore.
  8. The Fungal Cell Wall mannoproteins β1,6 glucans β1,3 chitin ergosterol β1,3 glucan synthase Cell membrane
  9. Ergosterol with pore Ergosterol Polyene
  10. Antifungal Spectrum z Candida albicans, Histoplasma capsulatum, Cryptococcus neoformans, Blastomyces dermatitidis, Coccidioides immitis, Aspergillus, Rhodotorula. z Resistance is rare and slow to develop z Pharmacokinetics z Poorly: crosses cell membranes, absorbed from the gut and penetration into the eye, CSF, and joint capsules z For treatment of meningitis, it must be given intrathecally Given only via IV injection or intrathecally Selective distribution into deep tissue sites, with slow release of drug Kidney > liver > spleen > lung > heart > skeletal muscle > brain > bone > CSF > eye
  11. z Classic amphotericin B deoxycholate (Fungizone™) formulation: serious toxic side effects. Less toxic preparations: 1) Liposomal amphotericin B 2) Amphotericin B colloidal dispersion 3) Amphotericin B lipid complex z milder acute reaction z better tolerated z lower nephrotoxicity z minimal anaemia z targeted delivery-liver & Spleen
  12. ADVERSE EFFECTS (AMB) z Acute: Infusion-related z Chills, fever, dyspnea, nausea, vomiting, bronchospasm, hypotension, convulsions z Chronic z Nephrotoxicity z impaired concentration, impaired urinary acidification, K & Mg wasting with hypokalemia and hypomagnesemia z Normochromic, normocytic anemia z (↓ erythropoietin)
  13. Drug interactions
  14. Griseofulvin z Fungistatic z A systemic antifungal used to treat topical ringworm infections, e.g., onychomycosis, Tinea capitis, Tinea pedis, etc. z many Trichophyton spp., Microsporum spp. and Epidermophyton spp. are susceptible z Dermatophyte infections z Oral absorption (better with small particle size) z Enzyme inducer
  15. Mode of Action - Griseofulvin z disrupts mitotic spindle during metaphase by interacting with fungal microtubules------ (-) fungal mitosis (metaphase arrest) z sufficient to inhibit growth of fungi (drug is static), preventing them from invading.
  16. Griseofulvin-Adverse actions z GI disturbances z Allergic reactions z Skin rash z Headache z Photosensitivity z Angioedema z Peripheral neuritis
  17. Griseofulvin-Adverse effects (CNS) z Lethargy z Mental confusion z Blurring of vision z Vertigo z Being an antimiototic--bone marrow suppression, leucopenia, neutopenia
  18. Griseofulvin-Uses
  19. 2. ANTIMETABOLITES: 5-Flucytosine (5-FC) z Flucytosine is converted into 5- flurouracil, which inhibits thymidylate synthetase leading to inhibition of DNA synthesis (antimetabolite action) z All susceptible fungi are capable of deaminating flucytosine to 5- flurouracil
  20. 3. AZOLES ‰ Better CSF penetrability ‰ High volume of distribution ‰ Dermatophytes, candida and other deep mycoses ‰ Triazoles are greater efficacy/lesser side effect and drug interaction
  21. 14- α demethylase Mechanism of Action: Acetyl CoA Squalene Lanosterol Ergosterol Azoles Squalene-2,3 oxide Squalene-2,3 epoxidase
  22. Effect of azoles on C. albicans Before exposure After exposure
  23. Ketoconazole z Spectrum: yeasts and moulds - poor absorption limits its role for severe infections, generally used in mucosal infections only z Pharmacokinetics z Variable oral absorption, dependent on pH (often given with cola or fruit juice) z T1/2 7-10 hours z Protein binding > 99% z Hepatic, bile and kidney elimination z H2 blockers, antacids--- decrease absorption
  24. 9Hepatoxicity (2-8%)- increase in transaminases, hepatitis 9Dose related inhibition of CYP P450- responsible for testosterone synthesis 9Dose-related inhibition of CYP P450 -responsible for adrenal cortisol synthesis
  25. 4. ALLYLAMINE: Terbinafine z It causes non- competitive inhibition of squalene epoxide enzyme, which is involved in the synthesis of ergosterol by fungi Squalene-2-3- epoxidase
  26. Mechanism of Action: 14-α demethylase Acetyl CoA Squalene Lanosterol Ergosterol Squalene-2,3 oxide Squalene-2,3 epoxidase Allylamines
  27. 4. ALLYLAMINE: Terbinafine z A highly lipophilic, keratinophilic z Effective orally against dermatophytes and candida z Useful in fungal infections of nails (6-12 weeks) z Adverse effects:- gastric upset, rashes and taste disturbances z Rarely hepatotoxicity
  28. 5. OTHER TOPICAL AGENTS: z White field’s ointment = Benzoic acid (6%) + Salicylic acid (3%) z Tolnaftate: Tinea corporis, cruris z Ciclopirox: Dermatophytes, candida Malassezia furfur z Selenium Sulfide: Malassezia furfur z Haloprogin: Dermatophytes, candida
  29. 1a 2 1 b 3 4
  30. What are the targets for antifungal therapy? Cell membrane Fungi use principally ergosterol instead of cholesterol Cell Wall Unlike mammalian cells, fungi have a cell wall DNA Synthesis Some compounds may be selectively activated by fungi, arresting DNA synthesis. Atlas of fungal Infections, Richard Diamond Ed. 1999 Introduction to Medical Mycology. Merck and Co. 2001
  31. 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)