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Antifungal agents

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

  • I was searching for a way to explain my recently frequent yeast infections and other related conditions stumbled upon your program on the internet. I suffered from chronic mouth thrush (with creamy white lesions on my tongue and inner cheeks). My baby daughter had the same problem in her mouth and your program was the only thing that helped us! I highly recommend your book to anyone who is perceptive about their health, and for those who are tired of being told that it's all in their heads. I feel so rejuvenated and lucky to have found this system. ■■■ http://scamcb.com/index7/pdf
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  • Hello, I'm 45 and have battled with severe Yeast Infection for the last nine years. A month and a half ago, I stumbled across your Yeast Infection No More program. I had my doubts and didn't think it was the right program for my Yeast Infection or if it was going to work at all, but I did order it because I'll do anything to rid myself of this crippling condition. Over 3 week period, I have seen an improvement that I had never experienced with any other conventional or so called natural treatment. The non-stop vaginal itching and burning have stopped. My skin looks significantly better and I slowly got rid of the psoriasis on my right elbow that I had for years. I can now save the money that I would have wasted on drugs like Monistat and Diflucan. Your suggestions have kept my vaginal yeast infections as well as the other candida related symptoms at bay incredibly well! I also lost about 15 lbs! I am feeling so healthy, too.  https://tinyurl.com/y3flbeje
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  • This program is a must read for anyone suffering from Candida or ones like me who has ever taken antibiotics and is now experiencing any of the many problems that go along with intestinal flora imbalance. I must also add that several people in my church have been following this book and are doing great! ◆◆◆ http://ishbv.com/index7/pdf
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  • About 2 years ago, I developed a severe case of vaginal yeast infection that would not let up. The itching, burning and swelling of my labia were simply unbearable. I have purchased several over-the-counter treatments, including Monistat cream to subside the symptoms. While it worked initially, eventually things wore off and left me with an even worse infection than before. The same goes for the antibiotics I took with the advice of my doctor. I felt horrible. After doing some research online, I guessed I had a yeast infection and purchased your program. The results were almost instantaneous. In less than 7 hours, I felt a tremendous relief. Two weeks later and I became completely free from the unbearable vaginal itching, burning, swelling and discharge. Using your methods, I have kept my chronic yeast infection at bay ever since. No more drugs or OTC�s for me. ♥♥♥ http://ishbv.com/index7/pdf
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  • Great book! I'm on the second week and seeing definite improvement on my yeast infection symptoms. I must also note that the texture of my skin became very soft and consistent. I completely agree with many of your arguments in the book especially those about conventional methods for treating Yeast Infection. I wanted to let you know that I feel so fine you have no idea. I am not so tired all the time and I feel very energetic. The rashes on my neck and on the right side of my nose have also cleared up. I wish you all the health and happiness in the world and thanks so much for helping me. I really appreciate your time and efforts to assist me. ♣♣♣ https://tinyurl.com/y3flbeje
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Antifungal agents

  1. 1. ANTIFUNGAL AGENTS -classification -MOA -indications -Adverse effects Susritha.k Pg dpt of ent ASRAMS eluru
  2. 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. 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. 4. Fungal infection SUPERFICIAL Dermatomycoses affecting skin, hair or nails. SYSTEMIC Candidiasis cryptococosis, Aspergillosis, Candidiasis Blastomycosis, Histoplasmosis, Coccidioidomycosi s, Paracoccidioidomy cosis
  5. 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. 6. iii) Allylamines Terbinafine Naftifine Butenafine vi) Echinocandins caspofungin
  7. 7. B)Drugs that inhibits mitosis Griseofulvin C)Drugs that inhibits DNA synthesis flucytosine Miscellaneous Haloprogi Tolnaftate Whitefield's ointment Ciclopirox olamine
  8. 8. Diagram showing mechanism of action of different anti fungal durgs
  9. 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. 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. 11.  Drug of choice for most systemic infections.  Course of treatment lasts 6-12 weeks.  Dose 0.5-1 mgkgday.
  12. 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. 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. 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. 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. 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. 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. 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. 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. 20.  Decrease in the ergosterol in the fungal membrane by ketoconazle reduces the fungicidal action of amphotericin.  Oral dose 400 mg daily.
  21. 21.  As it inhibits steroid biosynthesis, several endocrinological abnormalities may be evident as menstrual abnormalities, gynecomastia, decreased libido and impotency.  Contraindicated in pregnancy.
  22. 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. 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. 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. 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. 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. 27. GRISEOFULVIN  Isolated from Pencillium griseofulvum  It interacts with microtubules and interferes with mitosis.
  28. 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. 29. Comparison of Azoles fungistatic drugs
  30. 30. Topical anti fungal preparations  Topical       azole derivatives Ciclopirox olamine Naftifine Terbinafine Butenafine tolnaftate Nystatin and Amphotericin
  31. 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. 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. 33. Future prospects  Posaconazole azoles. & rabuconazole newer Very effective in treatment of zygomycosis in immunocompromised  Nikkomycins newer antifungals act by inhibiting chitin synthesis.
  34. 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. 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. 36. Bibliography  Goodmans gillmans-the pharmacological basis of therepeutics 10th edition pg:1295.  Principles of pharmacology –sharma h.s pg:789-90.  Tripati