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Course content 1 Chemotherapeutic agents Mechanism of actions Indications Contraindications/Cautions Drug interactions Side-effects/Adverse reactions Dosage regimen (occasionally) Reference Books 2 Pharmacology by Rang, Dale, Ritter, Gardner Clinical Pharmacology textbooks British National Formulary (BNF) 3 Antifungal agents 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 FUNGAL INFECTIONS 5 blastomycosis candidiasis histoplasmosis mucorymycosis ringworm Factors increasing incidence and severity 6 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) FUNGAL INFECTIONS 7 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 ANTIFUNGAL AGENTS 8 The Azoles Griseofulvin Flucytosine The polyenes Echinocandin antifungals (new) 9 I. Antifungals damaging permeability of 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 10 II. Antifungals inhibiting cell wall synthesis • Echinocandins: Caspofungin, anidulafungin and micafungin III. Antifungals inhibiting synthesis of nucleic acids • Flucytosine • Griseofulvin????? 11 AZOLES 12 Comprise the imidazoles and triazoles 13 Imidazoles: Miconazole Bifonazole Ketoconazole Butoconazole Clotrimazole Econazole Fenticonazole Tioconazole Isoconazole Oxiconazole Sertaconazole Sulconazole Triazoles: Fluconazole Itraconazole Ravuconazole Posaconazole Voriconazole 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 Azoles 15 Reduced fungal membrane ergosterol concentrations 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. KETOCONAZOLE 16 Spectrum of activity includes Candida species ٭ Coccidioides immitis ٭ Cryptococcus neoformans ٭ * Dermatophytes & Pityriasis versicolor Pharmacokinetics 17 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. KETOCONAZOLE 18 Metabolized through oxidation, dealkylation, aromatic hydroxylation. Excreted into the bile, faeces and the urine Bile Faeces Urine Side effects 19 Impotence Gynaecomastia Reduced sperm count Decreased libido Hepatotoxicity Nausea/vomiting Pruritis Dizziness Photophobia Contraindications/Precautions 20 Achlorhydria Hypochlorhydria Alcoholism Breast-feeding Children Hepatic disease Pregnancy Drug interactions 21 Antacids H2 blockers Omeprazole Isoniazid Corticosteroids Ethanol Phenytoin Rifampicin Astemizole Amphotericin B Miconazole, Econazole, Clotrimazole 22 Bioavailability is low when administered orally Usually used topically. Fluconazole 23 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. Fluconazole 24 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 Itraconazole 25 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, nonmeningeal blastomycosis and sporotrichosis Itraconazole 26 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. GRISEOFULVIN 27 Fermentation product of Penicillium griseofulvum 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. Griseofulvin also is deposited in keratin cells on the surface of the skin making it difficult for fungus to invade the skin and other tissues Pharmacokinetics 28 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 Drug Interactions 29 Barbiturates ( e.g. Phenobarbitone) Warfarin Oestrogen Progesterone preparations Toxicity and Side Effects 30 Headache Abdominal discomfort Rashes Fatigue, Dizziness (enhance effect of alcohol) Confusion and impaired co-ordination POLYENE ANTIFUNGALS 31 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 32 Toxic Effects 33 Anorexia, Nausea, Vomiting, diarrhoea, epigastric pain Headache, Muscle and Joint pain Disturbances in renal and liver functions Neurological and blood disorders Clinical Uses 34 Drug of choice in most systemic mycoses Candidiasis Cryptococcosis Aspergillosis Mucormycosis. Nystatin 35 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 Side Effects 36 Nausea Vomiting and Diarrhoea (at high doses) Oral irritation Rashes (topical and vaginal forms) Flucytosine (5-flucytosine, 5-FC) 37 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 thymidylate synthetase. Incorporation of these metabolites into fungal RNA inhibits protein synthesis. Indicated for :Crytococcus neoformans (Crytococcal), Candida infections (UTI’s) and Torulopsis glabrata 38 Pharmacokinetics 39 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 Side Effects 40 Leukopenia Thrombocytopenia Rash Nausea and vomiting diarrhoea. Severe enterocolitis Confusion, headache, sedation Drug Interactions 41 Amphotericin Cytotoxics Allylamines 42 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. 43 Terbinafine 44 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 Drug interactions 45 Rifampicin Cimetidine Famotidine Side effects 46 Abdominal discomfort Anorexia Urticaria rash Taste disturbance Photosensitivity ECHINOCANDIN ANTIFUNGALS 47 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. 48 Caspofungin 49 Pharmacokinetics Administration: IV 96% plasma protein bound Predominantly hepatic metabolism (hydrolysis and N-acetylation). Distribution: urinary concentration low, CSF concentration expected to be low Adverse effects 50 Fever Hepatotoxicity raised transaminases common in patients receiving caspofungin hepatic necrosis in animals given large