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Antifungal agents


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antifungal agents-mechanism of action-indications-adverse affects.

antifungal agents-mechanism of action-indications-adverse affects.

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  • 1. ANTIFUNGAL AGENTS -classification -MOA -indications -Adverse effects Susritha.k Pg dpt of ent ASRAMS eluru
  • 2.  Fungi are eukaryotic, heterotrophic (not self sustaining) organisms that live as saprobes or parasites.  They are complex organisms in comparison to bacteria.  Fungal infections are also called as mycoses.
  • 3.  They have nucleus and well defined nuclear membrane, and chromosomes.  they have rigid cell wall composed of chitin ( N – acetylglucosamine )  where as bacterial cell wall is composed of peptidoglycan .  fungal cell membrane contains ergosterol.
  • 4. Fungal infection SUPERFICIAL Dermatomycoses affecting skin, hair or nails. SYSTEMIC Candidiasis cryptococosis, Aspergillosis, Candidiasis Blastomycosis, Histoplasmosis, Coccidioidomycosi s, Paracoccidioidomy cosis
  • 5. Drug Classification A) Drugs that disrupt fungal cell membrane i) Polyenes Amphotericin Nystatin Natamycin ii) Azoles A) Imidazole Ketoconazole Butaxonazole Clotrimazole Econazole Miconazole Oxiconazole Sulconazole B) Triazole Fluconazole Itraconazole Tioconazole
  • 6. iii) Allylamines Terbinafine Naftifine Butenafine vi) Echinocandins caspofungin
  • 7. B)Drugs that inhibits mitosis Griseofulvin C)Drugs that inhibits DNA synthesis flucytosine Miscellaneous Haloprogi Tolnaftate Whitefield's ointment Ciclopirox olamine
  • 8. Diagram showing mechanism of action of different anti fungal durgs
  • 9. POLYENE ANTIBIOTICS  They act by: Binding to sterol in cell membrane. Deformity in plasma membrane occurs Interferes with permeability and with transport functions This allows leakage of intracellular ions and enzymes especially loss of intracellular k+ cell death.  They bind selectively to ergosterol in fungus but not in mammalian cell wall.
  • 10. AMPHOTERICIN B  It is macrolide antibiotic large lactone ring.  Poorly absorbed orally, useful for fungal infection of gastrointestinal tract.  Locally used in corneal ulcers, arthritis and candidial bladder irrigation  For systemic infections given as slow I/V infusion.  Highly protein bound.  Penetration through BBB is poor but increases in inflamed meninges.  Excreted slowly via kidneys, traces found in urine for months after cessation of drugs.  Half life 15 days
  • 11.  Drug of choice for most systemic infections.  Course of treatment lasts 6-12 weeks.  Dose 0.5-1 mgkgday.
  • 12. ADVERSE EFFECTS:  Most serious is renal toxicity, which occurs in 80% of patients.  Hypokalaemia in 25% of patients, requiring potassium supplementation.  Hypomagnesaemia Anemia Impaired hepatic function Thrombocytopenia   
  • 13. Liposomal preparations of amphotericin B(newer preparations)    To reduce the toxicity of amphotericin B ,several new formulations have been developed in which amphotericin B is packaged in a lipid-associated delivery system, to assume that they will less bind to mammalian cell. Lipid vehicle act as a reservoir, reducing binding to human cell. In this way it permits a larger doses, even five times more than colloidal preparation, they have better clearance .  Clinically they have more efficacy , less nephrotoxicity.  But these are very expensive.
  • 14. Nystatin  It is polyene macrolide,similar in structure to amphotericin and with same mechanism of action.  Too  Not toxic for systemic use absorbed from GIT /skin therefore administered orally.
  • 15.  Prevent or treat superficial candidiasis of mouth, esophagus or intestinal tract, oral suspension of 100,000 U/ml 4 times a day and tablets 500,000 U are used to decrease GIT colonization with Candida.  Can be used in combination with antibacterial agents and corticosteroids.
  • 16. AZOLES:  a bivalent chemical group composed of two nitrogen atoms.  They are antibacterial, antiprotozoal, anthelminthic and antifungal.  These are group of synthetic fungistatic agents.  They have broad spectrum of activity.  Inhibit the fungal cytochrome P450 3A enzyme , (lanosine 14-desmethylase ),which is responsible for converting lanosterol to ergosterol, the main sterol in the fungal cell membrane, this alters fluidity of the membrane, thus inhibiting the growth of fungi.
  • 17. IMIDAZOLES  Ketoconazole,  miconazole,  clotrimazole,  isoconazole ,  Tioconazole  They interfere with fungal oxidative enzymes to cause lethal accumulation of hydrogen peroxide.  they reduce the formation of ergosterol by inhibition of fungal cytochrome P450 enzyme, which become permeable to cellular constituent
  • 18. TRIAZOLES:    Fluconazole, itraconazole, voriconazole  They damage the fungal cell membrane by inhibiting enzyme desmethylase .  They are selective  Penetrate to CNS  Resistant to degradation  Cause less endocrine disturbance.
  • 19. KETACONAZOLE:  First azole that could be given orally to treat systemic fungal infections.  Well absorbed orally as acidic environment favours its dissolution.  Only administered orally.  After oral administration of 200,400 and 800 mg, plasma conc. reaches to 4.8 and 20 ug/ml.  Half mg life increases with dose and it is 7-8 hrs with 800
  • 20.  Decrease in the ergosterol in the fungal membrane by ketoconazle reduces the fungicidal action of amphotericin.  Oral dose 400 mg daily.
  • 21.  As it inhibits steroid biosynthesis, several endocrinological abnormalities may be evident as menstrual abnormalities, gynecomastia, decreased libido and impotency.  Contraindicated in pregnancy.
  • 22. ITRACONAZOLE     It is a synthetic triazole it is new drug It lacks endocrine side effects of ketoconazole. It has broad spectrum activirty  Administered orally as well as I/V.  Do not penetrate CSF adequately. Dose 100 mg twice daily with food, initially 300 mg thrice daily as a loading dose hypertriglyceridemia, Hypokalaemia, hepatotoxicty   FLUCONAZOLE  It is fluorinated bistriazole.  Completely absorbed from GIT  Excellent bioavailability by oral route.  Concentration in plasma is same by oral or I/v route Drug interactions are less common. It easily penetrate CSF and is a drug of choice in cryptococcal meningitis and coccido mycosis Candidiasis: 200 mg on 1st day then 100 mg daily for 2 weeks.     Cryptococcosis: 400 mg daily for 8 weeks in meningitis.  Hepatic failure may lead to death  It is highly teratogenic.
  • 23. Voriconazole  A new drug available in i.v and oral fromulations.  recommended dosage is 400 mg/ day  high biological availability when given orally  hepatic metabolism predominant.  it is similar to itraconazole but more potent.
  • 24. FLUCYTOSINE  Has useful activity against Candida and Cryptococcus.  it is synthetic pyrimidine antimetabolite that is often used in combination with amphotericin B.  Mechanism of action   It is converted to antimetabolite 5-florouracil in a fungal cell. This 5-FU inhibits thymidylate synthetase enzyme and thus DNA synthesis.
  • 25.  dose 100-150 mg /kg per day divided into 4 doses.  Generally use in combination with amphotericin  For cryptococcal meningitis in AIDS patients Side effects:   reversible neutropenia, thrombocytopenia and occasional bone marrow depression.
  • 26. Caspofungin  It is echinocandin class of antifungal drugs  it interferes with the synthesis of fungal cell wall by inhibiting synthesis of D-glucan.  especially useful for aspergillus and candida.  not active orally.  Has half life of 9-11 hours  Adverse  effects include nausea ,vomiting, flushing very expensive
  • 27. GRISEOFULVIN  Isolated from Pencillium griseofulvum  It interacts with microtubules and interferes with mitosis.
  • 28.  Uses   Mycotic diseases of skin, hair (particularly for scalp) , nail. It is also highly effective in athlete's foot Peripheral neuritis  Lethargy  mental confusion  impairment in performance of routine task  fatigue, vertigo ,syncope, blurred vision. 
  • 29. Comparison of Azoles fungistatic drugs
  • 30. Topical anti fungal preparations  Topical       azole derivatives Ciclopirox olamine Naftifine Terbinafine Butenafine tolnaftate Nystatin and Amphotericin
  • 31.  Amphotericin    B Candida oesphogitis0.15-0.2mg/kg daily. Invasive aspergillosis1-1.2mg/kg until progression is arrested. Candida cystitisbladder irrigation with 50ug/ml.
  • 32.  Itraconazoledeep   mycosis Divided dosage1st 3 days 200mg three times(loading dose) Maitainence dose200mg once daily for 12wks.  Flucanozole  Oesophageal candidiasis     200mg 1st day. 100mg daily for 2 wks. Coccidioial meningitis Cryptococcal meningitis400mg daily 8wks later 200mg for life
  • 33. Future prospects  Posaconazole azoles. & rabuconazole newer Very effective in treatment of zygomycosis in immunocompromised  Nikkomycins newer antifungals act by inhibiting chitin synthesis.
  • 34.  Sordarinsupcoming  Inhibits fungal growth by blocking elongation factor2.  Two   class of antifungals new echinocandins Micafungin Anidulafungin Effective in immunocomprimised pts against aspergillus & candida infections.
  • 35.  Recombinant form of human granulocyte colony stimulating factors like  Lenogastrin increase neutrophil count in neutropenia pts with fungal infections.  These are used along with antifungal agents to enhance their efficacy in immunocompromised pts.
  • 36. Bibliography  Goodmans gillmans-the pharmacological basis of therepeutics 10th edition pg:1295.  Principles of pharmacology –sharma h.s pg:789-90.  Tripati