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Anti-fungal drugs

  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 1. Topically  Oral, 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 1. 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 2. 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 2nd 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 t½, 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  Inhibit 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 Clotrimazole 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 Itraconazole or Fluconazole, that have largely replaced it for systemic use
  24. • M/c S/E Nausea and vomiting (can be reduced by giving the drug with meals) foll. by loss of appetite, headache, paresthesia, rashes and hair loss • Interactions  H2 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  1. Oral fluconazole (100 mg/day for 2 weeks) is highly effective in oropharyngeal candidiasis, but is reserved for cases not responding to topical antifungals 2. 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, H2 blockers and PPIs • Use  Preferred for most systemic mycosis not associated with meningitis • Seldom used in dentistry for oral candidiasis
  30. Voriconazole • 2nd 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  Gastric 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

Notas do Editor

  1. obtaining food by absorbing dissolved organic material especially : obtaining nourishment osmotically from the products of organic breakdown and decay
  2. Ergosterol is a sterol that resides on the cell membranes of fungi and acts to maintain cell membrane integrity, similar to mammalian cholesterol.
  3. Dermatophyte  a pathogenic fungus that grows on skin, mucous membranes, hair, nails, feathers, and other body surfaces, causing ringworm and related diseases.
  4. Intrathecal administration is a route of administration for drugs via an injection into the spinal canal, or into the subarachnoid space so that it reaches the cerebrospinal fluid (CSF) and is useful in spinal anesthesia, chemotherapy, or pain management applications.
  5. Thrush (oropharyngeal candidiasis) is a medical condition in which a yeast-like fungus called Candida albicans overgrows in the mouth and throat. Thrush may be triggered to occur by a variety of factors, including illness, pregnancy, medications, smoking, or dentures. Stomatitis is inflammation of the mouth and lips. It refers to any inflammatory process affecting the mucous membranes of the mouth and lips, with or without oral ulceration. In its widest meaning, stomatitis can have a multitude of different causes and appearances.
  6. Dermatophytes are aerobic fungi that can invade and infect the keratinized layers of skin, hair, and nails. Three genera of fungi, Trichophyton, Microsporum, and Epidermophyton, account for most dermatophytic infections. monilial. (məˈnɪlɪəl) adj. (Pathology) pathol denoting a thrush infection, caused by the fungus Candida (formerly Monilia) albicans
  7. Thrush (oropharyngeal candidiasis) is a medical condition in which a yeast-like fungus called Candida albicans overgrows in the mouth and throat. Thrush may be triggered to occur by a variety of factors, including illness, pregnancy, medications, smoking, or dentures.; colon
  8. Thrush (oropharyngeal candidiasis) is a medical condition in which a yeast-like fungus called Candida albicans overgrows in the mouth and throat. Thrush may be triggered to occur by a variety of factors, including illness, pregnancy, medications, smoking, or dentures.
  9. Thrush (oropharyngeal candidiasis) is a medical condition in which a yeast-like fungus called Candida albicans overgrows in the mouth and throat. Thrush may be triggered to occur by a variety of factors, including illness, pregnancy, medications, smoking, or dentures. Ringworm red, itchy, circular rash with clearer skin in the middle; tinea means fungal infection, whereas dermatophyte refers to the fungal organisms that cause tinea. Troche: A small medicated lozenge designed to dissolve. For example, to soothe the throat as a cough drop. Strictly speaking, a troche should be circular since the word derives from the Greek "trokhiskos" meaning "a little wheel.“Angular cheilitis is a condition that causes red, swollen patches in the corners of your mouth where your lips meet and make an angle
  10. Pityriasis versicolor is a fungal skin infection caused by a type of yeast. It's a common cause of skin rash in teens and young adults. It causes lots of round and oval-shaped patches on the skin, especially on the chest, back, and upper arms. It's also called tinea versicolor.
  11. Tingling or prickling, “pins-and-needles” sensation; usually temporary, often occurs in the arms, hands, legs or feet.
  12. Onychomycosis, also known as tinea unguium, is a fungal infection of the nail.
  13. Athlete's foot (tinea pedis) is a fungal infection that usually begins between the toes; Jock itch (tinea cruris) is a fungal infection that causes a red and itchy rash in warm and moist areas of the body. The rash often affects the groin and inner thighs and may be shaped like a ring. Jock itch gets its name because it's common in athletes.; Tinea corporis is a superficial dermatophyte infection characterized by either inflammatory or noninflammatory lesions on the glabrous skin (ie, skin regions other than the scalp, groin, palms, and soles) ; hairless; Tinea capitis is a disease caused by superficial fungal infection of the skin of the scalp, eyebrows, and eyelashes, with a propensity for attacking hair shafts and follicles.