1 / 58

Course content

Explore the mechanisms of antifungal agents, indications, contraindications, drug interactions, and side effects. Learn about different types of antifungals, such as azoles and their impact on fungal infections like candidiasis and ringworm. Discover dosage regimens, risks, and interactions for ketoconazole, fluconazole, and more.

ccallaghan
Download Presentation

Course content

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Course content Chemotherapeutic agents • Mechanism of actions • Indications • Contraindications/Cautions • Drug interactions • Side-effects/Adverse reactions • Dosage regimen (occasionally) C.Agyare

  2. Reference Books • Pharmacology by Rang, Dale, Ritter, Gardner • Clinical Pharmacology textbooks • British National Formulary (BNF) C.Agyare

  3. Antifungal agents C.Agyare

  4. Most fungi are commensals or live in the environment. • But increasing incidence and severity of human fungal infections • Fungal infections are termed mycoses and in Generally can be divided into: • 1) Superficial infections • 2) Cutaneous infections • 3) Sub-cutaneous infections • 4) Systemic infections C.Agyare

  5. FUNGAL INFECTIONS C.Agyare blastomycosis candidiasis histoplasmosis mucorymycosis ringworm

  6. Factors increasing incidence and severity of human fungal infections • Widespread use of broad-spectrum antibiotics (antimicrobial drugs) • Reduced immune responses caused by AIDS • Use of immunosuppressant drugs • Administration of anticancer drugs (cancer chemotherapy) • Chronic use of steroids (spreading of an infection) C.Agyare

  7. FUNGAL INFECTIONS . Fungal infections are usually more difficult to treat than bacterial infections • Fungal organisms grow slowly • Fungal infections often occur in tissues that are poorly penetrated by antimicrobial agents Eg: devitalized or avascular tissues C.Agyare

  8. ANTIFUNGAL AGENTS • The Azoles • Griseofulvin • Flucytosine • The polyenes • Echinocandin antifungals (new) C.Agyare

  9. Antifungalsdamaging permeabilityof the cell membrane • Imidazoles:Bifonazole, Clotrimazole, Econazole, Ketoconazole, Miconazole • Triazoles:Fluconazole, Itraconazole, Voriconazole • Allylamines:Terbinafine, Naftifine • Morpholines:Amorolfine • Thiocarbamates:Tolciclate, Tolnaftate • Substituted pyridones: Ciclopirox • Polyene antibiotics:Amphotericin B, Nystatin C.Agyare

  10. II. Antifungals inhibiting cell wall synthesis • Echinocandins: Caspofungin, anidulafungin and micafungin • III. Antifungals inhibiting synthesis of nucleic acids • Flucytosine • Griseofulvin????? C.Agyare

  11. C.Agyare

  12. AZOLES • Comprise the imidazoles and triazoles C.Agyare

  13. Imidazoles: • MiconazoleBifonazole • Ketoconazole Butoconazole • ClotrimazoleEconazole • FenticonazoleTioconazole • IsoconazoleOxiconazole • SertaconazoleSulconazole • Triazoles: • Fluconazole • Itraconazole • Ravuconazole • Posaconazole • Voriconazole C.Agyare

  14. Mechanism of action • Azoles inhibit the enzyme cytochrome P450 14α-demethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell membrane synthesis C.Agyare

  15. Azoles • Reduced fungal membrane ergosterolconcentrations result in damaged, leaky cell membranes • Azoles inhibiting cytochrome P450 enzymes (inhibits biosynthesis of adrenal and gonadal steroid hormones) • The toxicity of these drugs depends on their relative affinities for mammalian and fungal cytochrome P450 enzymes. • The triazoles tend to have fewer side effects, better absorption, better drug distribution in body tissues, and fewer drug interactions. C.Agyare

  16. KETOCONAZOLE • Spectrum of activity includes ٭Candida species ٭Coccidioides immitis ٭Cryptococcus neoformans * Dermatophytes & Pityriasis versicolor C.Agyare

  17. Pharmacokinetics • An acid environment is necessary for ketoconazole absorption • Administration of food with ketoconazole appears to increase absorption due possibly to: 1) increased bile secretions 2) delayed gastric emptying • Does not cross the intact blood-brain barrier except in meningitis. • Urinary concentrations of ketoconazole are usually low, but vaginal and vaginal tissue concentrations correlate with those in serum. C.Agyare

  18. KETOCONAZOLE Metabolized through • oxidation, • dealkylation, • aromatic hydroxylation. Excreted into the bile, faeces and the urine • Bile • Faeces • Urine C.Agyare

  19. Side effects • Impotence • Gynaecomastia • Reduced sperm count • Decreased libido • Hepatotoxicity • Nausea/vomiting • Pruritis • Dizziness • Photophobia C.Agyare

  20. Contraindications/Precautions • Achlorhydria • Hypochlorhydria • Alcoholism • Breast-feeding • Children • Hepatic disease • Pregnancy C.Agyare

  21. Drug interactions • Antacids • H2 blockers • Omeprazole • Isoniazid • Corticosteroids • Ethanol • Phenytoin • Rifampicin • Astemizole • Amphotericin B C.Agyare

  22. Miconazole, Econazole, Clotrimazole • Bioavailability is low when administered orally • Usually used topically. C.Agyare

  23. Fluconazole • Does not require an acidic environment, as does ketoconazole, for GI absorption. • About 80 to 90% absorbed from GIT. • Thet1/2 of the drug is 27 to 37 h, permitting once-daily • dosing in patients with normal renal function. • Only 11% of the circulating drug is bound to plasma proteins. C.Agyare

  24. Fluconazole • The drug penetrates widely into most body tissues eg CSF therefore effective for treating fungal meningitis. • About 80% of the drug is excreted unchanged in the urine. • Dosage reductions are required in the presence of renal insufficiency. • Alopecia and hepatic necrosis have been reported as adverse effects C.Agyare

  25. Itraconazole • Lipophilic and water insoluble • Requires a low gastric pH for absorption. • Oral bioavailability is variable (20 to 60%). • It is highly protein bound (99%) • Metabolized in the liver and excreted into the bile. • Useful in the treatment of disseminated histoplasmosis in AIDS,nonmeningealblastomycosis and sporotrichosis C.Agyare

  26. Itraconazole • Contraindicated in conditions of hepatic and renal impairment, pregnancy and breastfeeding mothers • Side effects include nausea, abdominal pain and rash. • Flatulence, constipation, menstrual disorders and alopecia may occur. C.Agyare

  27. GRISEOFULVIN • Fermentation product of Penicilliumgriseofulvum • Mode of action not exactly understood but involves nucleic acid synthesis and cell mitosis • Dermatophyte infections of the skin, scalp, hair and nails • Infections where susceptible strains of Trichophyton, Microsporum and Epidermaphyte are implicated. • Griseofulvinalso is deposited in keratin cells on the surface of the skin making it difficult for fungus to invade the skin and other tissues C.Agyare

  28. Pharmacokinetics • Well absorbed after oral administration. • Presence of fat in the diet appears increase absorption of griseofulvin • Metabolized in the liver and then excreted in urine C.Agyare

  29. Drug Interactions • Barbiturates ( e.g. Phenobarbitone) • Warfarin • Oestrogen • Progesterone preparations C.Agyare

  30. Toxicity and Side Effects • Headache • Abdominal discomfort • Rashes • Fatigue, Dizziness (enhance effect of alcohol) • Confusion and impaired co-ordination C.Agyare

  31. POLYENE ANTIFUNGALS Amphotericin B • Mechanism of Action: Destroys the integrity of cellular membrane of susceptible organism by binding to ergosterol • Active against most fungi and yeast • Treatment of systemic fungal infections. • Not absorbed from the gut • Given by IV infusion C.Agyare

  32. C.Agyare

  33. Toxic Effects • Anorexia, Nausea, Vomiting, diarrhoea, epigastric pain • Headache, Muscle and Joint pain • Disturbances in renal and liver functions • Neurological and blood disorders C.Agyare

  34. Clinical Uses • Drug of choice in most systemic mycoses • Candidiasis • Cryptococcosis • Aspergillosis • Mucormycosis. C.Agyare

  35. Nystatin • Produced from Streptomyces noursei • Active against Candida albicans infections of skin and mucous membranes • Not absorbed when given by mouth • Its activity is affected by long exposure to light, and heat C.Agyare

  36. Side Effects • Nausea • Vomiting and Diarrhoea (at high doses) • Oral irritation • Rashes (topical and vaginal forms) C.Agyare

  37. Flucytosine (5-flucytosine, 5-FC) • Fluorinated purimidine related to fluouracil and floxuridine • An analogue of cytosine that was originally synthesized for possible use as an antineoplastic agent. • 5-FC is converted to 5-fluorouracil inside the cell by the fungal enzyme cytosine deaminase. • The active metabolite 5-fluorouracil interferes with fungal DNA synthesis by inhibiting thymidylatesynthetase. • Incorporation of these metabolites into fungal RNA inhibits protein synthesis. Indicated for :Crytococcusneoformans (Crytococcal), Candida infections (UTI’s) and Torulopsisglabrata C.Agyare

  38. C.Agyare

  39. Pharmacokinetics • Rapidly and well absorbed in GI tract • Widely distributed in the body • Minimally bound to proteins • Approximately 80% excreted in the urine (unchanged) • Half-life 3-6 hours C.Agyare

  40. Side Effects • Leukopenia • Thrombocytopenia • Rash • Nausea and vomiting • diarrhoea. • Severe enterocolitis • Confusion, headache, sedation C.Agyare

  41. Drug Interactions • Amphotericin • Cytotoxics C.Agyare

  42. Allylamines • Reversible noncompetitive inhibitors of the fungal enzyme squalene epoxidase, which converts squalene to lanosterol. • These agents exhibit fungicidal activity against dermatophytesand fungistatic activity against yeasts. • Naftifine is available for topical use only in the treatment of cutaneous dermatophyte and Candida infections. C.Agyare

  43. C.Agyare

  44. Terbinafine • Dermatophyte infections of the nails and ringworm infections • Available for topical and systemic use • Lipophilic and highly binds to plasma protiens Cautions • Hepatic and renal impairment • Pregnancy • Breast feeding C.Agyare

  45. Drug interactions • Rifampicin • Cimetidine • Famotidine C.Agyare

  46. Side effects • Abdominal discomfort • Anorexia • Urticaria rash • Taste disturbance • Photosensitivity C.Agyare

  47. ECHINOCANDIN ANTIFUNGALS • Mode of action: inhibit ß-(1,3) glucan synthesis, damaging fungal cell walls • no drug target in mammalian cells • Rapidly fungicidal against most Candida spp. • Fungistatic against Aspergillus spp. • Active against cyst form of Pneumocystis carinii. C.Agyare

  48. C.Agyare

  49. Caspofungin Pharmacokinetics • Administration: IV • 96% plasma protein bound • Predominantly hepatic metabolism (hydrolysis and N-acetylation). • Distribution: urinary concentration low, CSF concentration expected to be low C.Agyare

  50. Adverse effects • Fever • Hepatotoxicity • raised transaminases common in patients receiving caspofungin • hepatic necrosis in animals given large doses (5-8 mg/kg) • Headache • Phlebitis • Rash (infrequent) • Haemolysis may occur but clinically significant haemolysis is rare C.Agyare

More Related