Anti-fungal drugs

Hello friends. In this PPT I am talking about anti-fungal drugs. If you like it, please do let me know in the comments section. A single word of appreciation from you will encourage me to make more of such videos. Thanks. Enjoy and welcome to the beautiful world of pharmacology where pharmacology comes to life. This video is intended for MBBS, BDS, paramedical and any person who wishes to have a basic understanding of the subject in the simplest way.

1. Anti-fungal drugs Dr. Karun Kumar Senior Lecturer Dept. of Pharmacology

2. Anti-fungal drugs Drugs used for superficial and deep ( systemic) fungal infections Fungal infections are mostly associated with the use of broad-spectrum antibiotics, corticosteroids, anticancer/immunosuppressant drugs , dentures , indwelling catheters and implants, and emergence of AIDS

3. As a result of breakdown of host defence mechanisms by the above agents , saprophytic fungi easily invade living tissue C. albicans is normally resident in the oral cavity It invades to cause inf. when host defence is impaired or the oral flora is disturbed

4. Classification

5. Polyene antibiotics The name polyene is derived from their highly double-bonded structure Amphotericin B (AMB )  Not abs. orally Cholesterol, present in host cell membranes , closely resembles ergosterol ; the polyenes bind to it as well, though with lesser affinity Selectivity of action of polyenes is low, and AMB is one of the most toxic systemically used antibiotics

6. Bacteria do not have sterols and are unaffected by polyenes Active against a wide range of yeasts and fungi—Candida albicans , Histoplasma capsulatum , Cryptococcus neoformans , Blastomyces dermatitidis , Coccidioides immitis , Torulopsis , Rhodotorula , Aspergillus , Sporothrix , etc.

7. Dermatophytes are inhibited in vitro, but concentrations of AMB attained in infected skin are low and ineffective It is fungicidal at high and static at low concentrations Also active on various species of Leishmania , a protozoa

8. Uses Topically  O ral , vaginal and cutaneous candidiasis; otomycosis Most effective drug for various types of systemic mycoses and is the gold standard of antifungal therapy However , because of higher toxicity of AMB, the azole antifungals are now preferred 2. Leishmaniasis

9. Adverse effects Acute reaction  Occurs with each infusion and consists of chills, fever, aches and pain all over, nausea, vomiting and dyspnoea lasting for 2–5 hour, probably due to release of cytokines (IL, TNFα). Thrombophlebitis of the injected vein can occur Long-term toxicity  Nephrotoxicity is the most important . Most patients develop slowly progressing anemia (bone marrow depression)

10. Nystatin It is similar to AMB in antifungal action and other properties However, because of higher systemic toxicity , it is used only locally in superficial candidiasis In dentistry, topically applied Nystatin is 2 nd choice drug to Clotrimazole for oral thrush, denture stomatitis, a.b . assoc. stomatitis, c.s . assoc. oral candid., mucocut . candid. of lips

11. 1 lac U (1 mg = 2000 U) tab is placed in mouth to dissolve slowly 4 times a day or it can be crushed and suspended in glycerine for application on the lesions in mouth. S/E  Bitter foul taste and nausea Corticosteroid aerosols (e.g. Beclomethasone ) can cause oral candidiasis: nystatin is effective in preventing as well as treating it

12. Nystatin is effective (but less than azoles ) in monilial vaginitis—1 lac U tab inserted twice daily Similarly, it is used for corneal, conjunctival and cutaneous candidiasis in the form of an ointment Ineffective in dermatophytosis Given orally, not abs. (used in monilial diarrhoea )

13. Imidazoles and Triazoles Most extensively used antifungal drugs Fluconazole and Itraconazole have replaced Ketoconazole for systemic mycosis because of greater efficacy, longer t ½, fewer side effects and drug interactions Posaconazole is a new triazole to be used as a reserve drug for non- responsive cases

14. The Imidazoles and triazoles have broad spectrum antifungal activity covering dermatophytes , Candida, other fungi involved in deep mycosis, Nocardia and Leishmania MOA  I nhibit the fungal cytochrome P450 enzyme ‘ lanosterol 14-demethylase ’ and impair ergosterol synthesis leading to a cascade of membrane abnormalities in the fungus

15. The lower host toxicity of triazoles compared to imidazoles has correlated with their lower affinity for mammalian CYP450 enzymes and lesser propensity to inhibit mammalian sterol synthesis Development of fungal resistance to azoles has not so far posed any significant clinical problem

16. Clotrimazole Effective in the topical t/t of tinea infections like ringworm, Athletes ’ foot and otomycosis Oral/cutaneous/vaginal candidiasis have responded in >80 % cases . M/c used drug for oropharyngeal candidiasis 10 mg troche of clotrimazole is allowed to dissolve in the mouth 3–4 times a day, or the lotion/gel is applied/swirled in the mouth for as long as possible.

17. For denture stomatitis, pts. are advised to apply Clotrimazole lotion/gel to the fitting surface of the denture before wearing it Also, the denture should be kept overnight in sod. hypochlorite/ Benzalkonium / Cetrimide soln. and it should be worn only when needed.

18. Topical Clotrimazole can be used to treat angular cheilitis that often is a mixed candidal , streptococcal, staph. inf. Clotrimazole is well tolerated by most patients Local irritation with stinging and burning sensation occurs in some No systemic toxicity is seen after topical use

19. Ringworm infection

20. Econazole It is similar to Clotrimazole ; penetrates superficial layers of the skin and is highly effective in dermatophytosis , otomycosis , oral thrush, but is somewhat inferior to C lotrimazole in vaginitis No adverse effects , except local irritation in few is reported

21. Miconazole It is a highly efficacious (>90 % cure rate) drug for tinea , pityriasis versicolor , otomycosis , cutaneous and vulvovaginal candidiasis Single application on skin acts for a few days Irritation after cutaneous application is infrequent No systemic adverse effects are seen

22. Oxiconazole A newer topical imidazole antifungal effective in tinea and other dermatophytic infection, as well as vaginal candidiasis Local irritation can occur in some patients

23. Ketoconazole Orally effective broad-spectrum antifungal drug Useful in dermatophytosis , superficial candidiasis and deep mycosis Oral absorption facilitated by gastric acidity Dose  200 mg OD or BD A/E less than with AMB, but more side effects occur than with I traconazole or Fluconazole , that have largely replaced it for systemic use

24. M/c S/E N ausea and vomiting (can be reduced by giving the drug with meals) foll . by loss of appetite, headache, paresthesia , rashes and hair loss Interactions  H 2 blockers, PPIs & antacids ↓ oral abs. of KTZ by reducing gastric acidity . Rifampin , phenobarbitone , carbamazepine and phenytoin induce KTZ metabolism and reduce its efficacy Use  Rarely used in dental practice

25. Fluconazole Wider range of activity than KTZ ; indications include cryptococcal meningitis , systemic and mucosal candidiasis in both normal and immunocompromised patients, coccidioidal meningitis and some tinea infections Fungicidal conc. are achieved in nails, vagina and saliva; penetration into brain and CSF is good

26. A/E  Fluconazole produces fewer side effects: mostly nausea, vomiting, abdominal pain, rash and headache. Not recommended in pregnant and lactating mothers Interactions  Same as KTZ

27. Use  Fluconazole can be administered orally as well as i.v. (in severe infections ) In dentistry  Oral fluconazole (100 mg/day for 2 weeks ) is highly effective in oropharyngeal candidiasis , but is reserved for cases not responding to topical antifungals Fluconazole (100 mg/day) for 2–3 weeks is the first line treatment for Candida esophagitis

28. Itraconazole Broader spectrum of activity than KTZ or Fluconazole ; includes some moulds like Aspergillus and some fluconazole resistant Candida Fungistatic , but effective in immunocompromised patients Oral abs. enh . by food and gastric acid Well tolerated in doses below 200 mg/day.

29. Gastric intolerance is significant at > 400 mg/day. Dizziness, pruritus, headache and hypokalaemia are the other common S/E Drug interactions  Oral abs. ↓ by antacids, H 2 blockers and PPIs Use  P referred for most systemic mycosis not associated with meningitis Seldom used in dentistry for oral candidiasis

30. Voriconazole 2 nd gen. broad spectrum for difficult to treat fungal infections like invasive aspergillosis , disseminated infections caused by Fluconazole resistant Candida, Fusarium infections and febrile neutropenia not responding to antibacterial therapy Serious cases are first treated i.v . A/E  Rashes , visual disturbances, QTc prolongation and an acute reaction on i.v. injection

31. Terbinafine ( Allylamine ) Fungicidal Noncompetitive inhibitor of ‘ squalene epoxidase ’, Accumulation of squalene within fungal cells  fungicidal action High affinity for keratin (conc. in stratum corneum of skin & nail plates  Effective in tinea inf. Of skin and nails ) S/E  G astric upset, rashes, taste disturbance Topical terbinafine can cause erythema , itching , dryness, irritation, urticaria and rashes

32. Use  Terbinafine applied topically as 1% cream twice daily is indicated in localized tinea pedis / cruris / corporis and pityriasis versicolor 2–4 weeks treatment is required Oral treatment with 250 mg OD is reserved for onychomycosis , tinea capitis and wide spread lesions Duration of treatment varies from 3–6 months or more Less effective against cutaneous and mucosal candidiasis: 2–4 weeks oral therapy may be used as an alternative to fluconazole

33. Tinea capitis

34. Tinea cruris

35. Tinea pedis

36. Tinea corporis