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Antifungal agents

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Antifungal agents

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Antifungal agents

  1. 1. Dr.Elza Joy Munjely JR-I Depmt. Of Pharmacology Govt. Medical College,Kottayam.
  2. 2. Fungi- Eukaryotes
  3. 3. Cell wall- beta glucan and chitin Cell membrane – ergosterol
  4. 4. 1. Yeasts – Crypyococcus neoformans 2. Yeast –like fungi- Candida albicans 3. Moulds- Dermatophytes 4. Dimorphic fungi- Blastomyces dermatitidis, Histoplasma capsulatum, Coccidioides immitis, Sporothrix Pathogenic Fungi Classification
  5. 5. Fungal infections – Mycoses SUPERFICIAL-Black piedra CUTANEOUS-Tinea SUBCUTANEOUS-Sporotrix SYSTEMIC- Blastomycosis, Histoplasmosis, Coccidioidomycosis, Cryptococcosis OPPORTUNISTIC – Mucor,Aspergillus,Candida
  6. 6. Classification based on mechanism of action 1. Acting on fungal cell wall : Echinocandins. 2. Acting on fungal cell membrane : Polyenes,Azoles & Allylamine 3. Inhibition of nucleic acid synthesis: 5– Flucytosine.
  7. 7. 4.Acting on mitotic spindle: Griseofulvin. 5.Topical: Ciclopirox, Tolnaftate, Haloprogin, Undecylenic acid, Topical azoles.
  8. 8. MECHANISM OF ACTION
  9. 9. ANTIFUNGALS ALTERATION OF CELL MEMBRANE / WALL PROPERTIES BLOCK NUCLEIC ACID SYNTHESIS INHIBIT MICROTUBULE FUNCTION Porin- Formation Synthesis inhibitors Polyene antibiotics  Amphotericin B  Nystatin Flucytosine Griseofulvin 1.Azoles 2.Allylamines 3.Glucan synthesis inhibitors Mechanism of action of Echinocandins
  10. 10. MOA of Polyenes
  11. 11. Amphotericin B Binds ergosterol in fungal cell membrane Form pores in cell membrane Cell contents leak out Cell death
  12. 12. Precursors Squalene Lanosterol ergosterol 14--demethylase Squalene epoxidase Fungal cell membrane AZOLES & ALLYLAMINES Allylamines Azole antifungals
  13. 13. MOA of flucytosine
  14. 14. MOA of Griseofulvin Binds to polymerised microtubules and inhibit mitosis
  15. 15. Squalene Lanosterol Ergosterol Squalene epoxide 14-- demethylase 5-FC 5-FU 5-FdUMP dUMP dTMP DNA Cytosine deaminase Thymidylate synthetase microtubules Pore formation Permease Fungal cellwall cell membrane ECHINOCANDINS AMPHOTERICIN B ALLYLAMINES AZOLES GRISEOFULVIN FLUCYTOSINE FUNGAL CELL
  16. 16. Polyene antibiotics  Amphotericin B:  Streptomyces Nodosus  Amphoteric Lactone ring Lipophilic part Hydrophilic part
  17. 17. Antifungal spectrum - Aspergillus - Blastomyces dermatitidis - Candida albicans - Cryptococcus neoformans - Coccidioides immitis - Histoplasma capsulatum - Mucor spp. - Broadest spectrum of action
  18. 18. Liposomes in the therapy of infectious diseases and cancer 1989: 105 Antiprotozoal spectrum •Leshmania •Naegleria fowleri
  19. 19. Mechanism of resistance Replacement of ergosterol by other sterols in fungal plasma membrane.
  20. 20. Pharmacokinetics Poorly absorbed orally Insoluble in water so colloidal suspension prepared with sodium deoxycholate(1:1 complex) t ½ = 15 days
  21. 21. Lıpıd formulations of amphotericin B (ABLC; Abelcet®) (ABCD; Amphocil® or Amphotec®) (L-AMB; Ambisome®) Amphotericin B Lipid Complex(ABLC) Amphotericin B Colloidal Dispersion(ABCD) Liposomal Amphotericin B
  22. 22. Ribbon-like particles Carrier lipids: DMPC, DMPG J Liposome Res 1993; 3: 451 AMB Lipid complex (ABLC): ABLC
  23. 23. ABCD AMB colloidal dispersion (ABCD):
  24. 24. The ‘LIPOSOME’.. Hospital Practice 1992; 30: 53 •Liposomal AMB (Small unilamellar vesicles) :
  25. 25. • Adverse events: –Acute reaction: –Long term toxicity: –Nephrotoxicity: –CNS toxicity : –Anaemia –Hepatotoxicity rarely
  26. 26. • Systemic mycotic infections • invasive aspergillosis • Rapidly progressive Blastomycosis & Coccidiomycosis • Mucormycosis. • Disseminated rapidly progressing Histoplasmosis • Cryptococcus neoformans-intra thecal •Given as IV Available as 50mg vial – suspended in 10 ml water and then diluted with 500 ml glucose Uses
  27. 27. Liposomes in the therapy of infectious diseases and cancer 1989: 105 Release from macrophage Macrophage Release in blood compartment Endocytosis Liposome Lysosome Fusion Liposome degradation Endocytic vesicle Reserve drugs for resistant kala azar
  28. 28. Topical uses  Intestinal Monoliasis: Orally  Vaginitis  Otomycosis: 3 % drops  Mycotic infections of the bladder (bladder irrigation)
  29. 29. Nystatin  S.Noursei  locally Uses:  Intestinal moniliasis  Vaginitis  Prevention of oral candidiasis  Oral, cutaneous, conjunctival candidiasis
  30. 30. Hamycin:  S. Pimprina  Hindustan antibiotics Topical use in thrush, cutaneous candidiasis, trichomonas & monilial vaginitis, otomycosis by aspergillus
  31. 31. Natamycin: Broad spectrum Used topically Fusarium solani keratitis, trichomonas & monilial vaginitis
  32. 32. AZOLES Synthetic Broad spectrum Fungistatic or fungicidal depending on conc of drug  imidazoles & triazoles
  33. 33. Imidazoles:  Two nitrogen in structure  Topical: econazole, miconazole, clotrimazole  Systemic : ketoconazole  Newer : butaconazole, oxiconazole, sulconazole
  34. 34. Triazoles Three nitrogen in structure  Fluconazole, itraconazole, voriconazole Terconazole
  35. 35. SYSTEMIC TOPICAL  Ketoconazole  Fluconazole  Itraconazole  Voriconazole  Clotrimazole  Miconazole  Econazole  Oxiconazole  Sertaconazole  Terconazole  Sulconazole  Tioconazole  Butaconazole
  36. 36. Imidazoles
  37. 37. Miconazole & clotrimazole  Topical use:  Miconazole 2 % and clotrimazole 1 %  Uses:  Dermatophyte infections  Candida: oral pharyngeal, vaginal, cutaneous  Adverse events:  Local irritation
  38. 38. First orally effective broad spectrum antifungal acidic environment favours absorption Csf penetration less Ketoconazole
  39. 39. Adverse events of ketoconazole ↓ steroid, testosterone & estrogen synthesis Gynaecomastia, oligospermia , loss of libido & impotence in males Menstrual irregularities & amenorrhoea in females
  40. 40. Drug Interactions of ketoconazole
  41. 41. Dangerous interaction with terfenadine,astemizole and cisapridePolymorphic ventricular tachycardia
  42. 42. Ketoconazole and steroid hormone synthesis  Inhibit cholesterol side-chain cleavage enzyme 17α-hydroxylase -which converts cholesterol to pregnenolone 17,20-lyase ,which convert pregnenolone into androgens  11β-hydoxylase, which converts 11- deoxycortisol to cortisol.
  43. 43. Uses of ketoconazole Dermatophytosis: conc in stratum corneum Monilial vaginitis : Systemic mycosis Topical: T.pedis, cruris, corporis, versicolor
  44. 44. Other uses of ketoconazole Prostate cancer Precocious puberty Cushing syndrome Hirsuitism
  45. 45. Triazoles
  46. 46. Fluconazole  Broad spectrum  Candida, cryptococcosis, coccidiodomycosis  Dermatophytosis  Blastomycosis  Histoplasmosis  Sporotrichosis  Oral, IV as well as topical  Not effective against aspergillosis & mucormycosis
  47. 47. Pharmacokinetics of fluconazole Not affected by food or gastric pH crosses BBB –Fungal meningitis
  48. 48. Adverse events of fluconazole GIT upset Less adverse effects than ketoconazole No anti androgenic & other endocrine effects
  49. 49. Uses of fluconazole  Candida:  vaginal candidiasis- 150 mg oral dose  Oral candidiasis- 2 weeks treatment required  Tinea infections & cutaneous candidiasis: • 150 mg weekly for 4 weeks • tinea unguim : 12 months  Systemic fungal infections: Meningitis: preferred drug  Eye drops for fungal keratitis
  50. 50. Itraconazole Broad spectrum of activity also against aspergillus Does not inhibit steroid hormone synthesis and no serious hepatoxicity
  51. 51. Pharmacokinetics of itraconazole  Absorption enhanced by food & gastric acidity  Accumulates in vaginal mucosa, skin, nails  CNS penetration is poor  Metabolized in liver
  52. 52. Uses of itraconazole DOC for paracoccidomycosis & chromoblastomycosis , histoplasmosis & blastomycosis Also used in oesophageal, oropharyngeal vaginal candidiasis Dermatophytosis Onychomycosis Aspergillosis
  53. 53. Adverse events of itraconazole  Hypokalemia  Increase plasma transaminase  Drug interactions:  Oral absorption ↓by antacids, H2 blockers
  54. 54. Voriconazole High oral bioavailability Good CSF penetration Doesn’t require gastric acidity for absorption
  55. 55. Uses of voriconazole DOC for invasive aspergillosis Most useful for esophageal candidiasis First line for moulds like fusarium Resistant candida infections
  56. 56. Adverse effects of voriconazole Adverse events: Transient visual changes like blurred vision , altered color perception & photophobia Prolongation of QT
  57. 57. Posaconazole Broadest spectrum azole Liquid oral formulation Dose : 800mg/day Potent inhibitor of CYP-3A4
  58. 58. Indications -Posaconazole Prophylaxis of invasive candidiasis Salvage therapy for invasive aspergillosis Mucor mycosis & zygomycosis – the only azole active!
  59. 59. Ravuconazole Phase II clinical trial Spectrum- Candida sp Aspergillus Dermatophytes Oral
  60. 60. Water solubility Absorption Halflife(hrs ) Eliminatio n Formulatio ns Ketoconazole low variable 7-10 Hepatic Oral itraconazole low variable 24-42 Hepatic Oral/IV Fluconazole high high 22-31 Renal Oral/IV Voriconazole high high 6 Hepatic Oral/IV Posaconazole low high 25 Hepatic Oral
  61. 61. VORICONAZO LE POSACONAZOL E RAVUCONAZOL E Formulations ORAL/IV ORAL ORAL T 1/2 6 hrs 25 hrs 100 hrs Adverse effects liver enz Visual S/E GI upset Hepatotoxic Drug interactions High least
  62. 62. Terbinafine Orally & topically effective Fungicidal Pharmacokinetics: Well absorbed orally Highly keratophilic & lipophilic poor BBB permeability t1/2- 15 days
  63. 63. Adverse events and uses Adverse events: Taste disturbances Rarely hepatic dysfunction Uses: Dermatophytosis Onychomycosis Candidiasis
  64. 64. Other allylamines Naftifine  Dermatophytes,T.versicolor,cutaneous candidiasis Butenafine
  65. 65. 5 flucytosine Narrow spectrum Prodrug, pyrimidine analog Adverse events:  Bone marrow toxicity , Alopecia, rarely hepatitis Uses: in combination with AMB in cryptococcal meningitis
  66. 66. Advantages of combination: –Entry of 5 FC –Reduced toxicity –Rapid culture conversion –Reduced duration of therapy –Decreased resistance
  67. 67. Griseofulvin Penicillium griseofulvum Fungistatic  systemic drug for superficial fungal infections Active against dermatophytes Dermatophytes concentrate it actively hence selective toxicity
  68. 68. Pharmacokinetics: Increased absorption by fatty food  keratinized tissue t1/2=24 hrs
  69. 69.  Adverse events:  Headache most common  CNS symptoms: confusion, fatigue, vertigo  Peripheral neuritis  photoallergy  Transient leukopenia, albuminuria
  70. 70.  Uses: Systemically only for dermatophytosis, ineffective topically Duration of treatment depends on site, thickness of keratin and turnover of keratin. Treatment must be continued till infected tissue is completely replaced by normal skin,hair, nail. Dose: 125-250 mg QID
  71. 71. Duration of treatment • Body skin = 3 weeks • Palm, soles = 4- 6 weeks • Finger nails = 4- 6months • Toe nails = 8 – 12 months
  72. 72.  Interactions:  Warfarin , OCP  Phenobarbitone, Disulfiram like reaction
  73. 73. Echinocandins  Spectrum Candida Aspergillus NOT active againt Cryptococcus PK  Highly PPB  Metabolites are eliminated by kidneys & GIT  Available only as i/v formulations
  74. 74. Echinocandins Adv Broad -spectrum activity against all Candida species Relatively low toxicity- among the safest
  75. 75. Caspofungin FDA approved in 2001 Dose – single loading dose 70mg followed by daily dose of 50mg iv over 1 hr Use Invasive forms of candidosis Candidemia Invasive aspergillosis
  76. 76. Micafungin FDA- approved in 2005 Candida esophagitis- 150 mg/day Candidemia -100mg/day Prophylaxis of fungal infections in those receiving stem cell transplant- 50mg/day D/I Micafungin -↑ the levels of nifedipine,cyclosporine and sirolimus
  77. 77. Anidulafungin FDA approved in2006 Candida esophagitis- 100mg 1st day followed by 50mg/day Candidemia- 200mg 1st day followed by 100mg/day
  78. 78. Adverse Effects  Flushing , phlebitis-Anidulafungin  Increase in liver enz.  GI disturbances Caspofungin
  79. 79. Topical agents used in dermatophytosis  Tolnaftate:  Tinea infections.  Not effective in hyperkeratinized lesions  Salicylic acid aids its effect by keratolysis
  80. 80. Topical agents used in dermatophytosis  Ciclopirox olamine:  Tinea infections, pitryasis versicolor ,dermal candidiasis, vaginal candidiasis  Penetrates superficial layers
  81. 81. Topical agents used in dermatophytosis Undecylenic acid: 5% (Tineafax) Generally combined with zinc (20%) used in tinea cruris and nappy rash Sodium thiosulfate: (Karpin lotion) Reducing agent known as hypo Effective in pitryasis versicolor only 20 % solution for 3-4 weeks
  82. 82. Topical agents used in dermatophytosis  Benzoic acid:  Used in combination with salicylic acid  Whitfields ointment: ( benzoic acid 6% + salicyclic acid 3 %)  Salicyclic acid due to its keratolytic action helps to remove infected tissue & promotes penetration of benzoic acid in fungal infected lesion  Adverse events: irritation & burning sensation (Ring cutter ointment)
  83. 83. Topical agents used in dermatophytosis Haloprogin  Dermatophytosis  Mainly-T.pedis
  84. 84. Topical agents used in dermatophytosis Quinidiochlor; Luminal amoebicide Weak antifungal & antibacterial External application : dermatophytosis , mycosis barbae, pitryasis versicolor Selenium sulfide: T. versicolor  Potassium iodide: Dermatophytic infection
  85. 85. Spectrum of action Nystatin: Candidiasis only Griseofulvin: Dermatophytosis only Terbinafine : Dermatophytosis & candidiasis Caspofungin: Aspergillosis & candidiasis
  86. 86. Important characteristics • Broad spectrum: AMB, KTZ, FLU, ITR • Nephrotoxic/ Anemia: AMB • Leucopenia: 5 FC • GIT upset: All • Over all toxicity: highest for AMB lowest for fluconazole, itraconazole

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