AntiFungal Drugs Pharm Exam 2 PDF

Antifungal drugs Classification ○ Polyene abx (e.g., amphotericin B) ○ Azole derivatives (e.g., clotrimazole, fluconazole AKA Diflucan) ○ Allylamine drugs (e.g., terbinafine aka Lamisil) ○ Echinocandin drugs (e.g., caspofungin) ○ Other antifungal...

Antifungal drugs Classification ○ Polyene abx (e.g., amphotericin B) ○ Azole derivatives (e.g., clotrimazole, fluconazole AKA Diflucan) ○ Allylamine drugs (e.g., terbinafine aka Lamisil) ○ Echinocandin drugs (e.g., caspofungin) ○ Other antifungal agents Fungal infections ○ Divided into three main groups… 1. Systemic mycoses (e.g., soft tissue infections, UTIs, PNA, meningitis, septicemia) 2. Subcutaneous mycoses (e.g., sporotrichosis) 3. Superficial mycoses (i.e., infections of nails, skin and mucous membranes caused by dermatophytes are yeasts) Superficial dermatophyte infections ○ Causative agents are Epidermophyton, Microsporum, and Trichophton spp. ○ Many different terms are used to describe the infection ○ Typically manifest as rash with pruritus and erythema ○ Ringworm presents as annular, scaly rash with clear center Term for dermatophyte infections ○ Onychomycosis, tinea unguium – dermatophyte infection of nails ○ Tinea pedis – athlete’s foot ○ Tinea corporis – ringworm of the body ○ Tinea cruris – jock itch Superficial yeast infections ○ Causative agents are candida spp., usually C. albicans ○ Present as oral candidiasis (thrush), vulvovaginal candidiasis, or candidiasis infections of axilla, groin or gluteal folds (diaper rash) ○ Less common causes are M. furor and M. ovalis ○ M. furfur causes tinea versicolor (also called pityriasis versicolor) ○ Both yeasts cause seborrheic dermatitis Subcutaneous mycoses ○ Often caused by puncture wounds contaminated with soil fungi ○ Examples include chromomycosis, pseudallescheriasis, and sporotrichosis Systemic mycosis ○ Chronic and indolent (e.g., blastomycosis, coccidioidomycosis, and histoplasmosis) ○ Invasive and life-threatening (e.g., aspergillosis, candidiasis, cryptococcosis, and mucormycosis) Blastomycosis  ○ Fungal infection of humans and other animals (dogs, cats) caused by blastomyces dermatitidis ○ Endemic to north america ○ Clinical symptoms similar to histoplasmosis ○ Flu-like illness, acute illness resembling bacterial PNA, chronic illness mimicking TB/lung cancer, fast progressive disease like ARDS, skin lesions, bony lytic lesions… Coccidioidomycosis ○ Aka “valley fever”, “california fever”, and “san Joaquin valley fever” ○ Fungal disease caused by coccidioides immitis or coccidioides posadasii ○ Endemic in certain parts of Az, CA, NV, NM, TX, UT, and northern mexico ○ 60% are asymptomatic, 40% have varied symptoms… Classic triad (“desert rheumatism”) of fever, joint pain, and erythema nodosum. Histoplasmosis ○ Aka “cave disease”, “spelunker’s lung”, “Ohio valley disease” ○ Fungal infection caused by histoplasma capsulatum ○ Found in soil, often associated with decaying bat guano or bird droppings ○ Primarily affects lungs, called disseminated when other organs affected ○ Can be fatal if left untreated Aspergillosis ○ Wide variety of disease caused by fungi from genus aspergillus ○ Majority of cases in people with underlying TB or COPD but with otherwise health immune systems ○ M/C occurs in form of chronic pulmonary aspergillosis, aspergilloma, or allergic bronchopulmonary aspergillosis Cryptococcosis ○ Potentially fatal fungal disease caused by cryptococcus neoformans and cryptococcus gattii ○ Acquired by inhalation of infectious material from environment; found in worldwide in soil ○ Defining opportunistic infection for AIDs (but also seen with lymphomas, sarcoid, liver cirrhosis, and patient on long term steroid therapy) Mucormycosis ○ Any fungal infection cuased by fungi in the order of mucorales ○ Characterized by hyphae growing in and around blood vessels; potentially life-threatening in diabetic or severely immunocompromised Treating fungal infections ○ Amphotericin B is typically used to treat severe mycoses ○ Azoles are used for less severe infections  ○ New agents (e.g., voriconazole and caspofungin) can be used to treat invasive Candida and aspergillus infections ○ Flucytosine is usually given with amphotericin B to treat systemic cryptococcus or candida infections Polyene Antibiotic Amphotericin B aka Amphotec Natamycin Nystatin Kinetics ○ Amphotericin B is not absorbed from the gut ○ Available for topical and parenteral use ○ Dosage and route of parenteral treatment depends on site and severity of infection ○ Low concentration in CSF because it doesn't penetrate BBB well ○ Metabolized by liver, excreted in urine ○ Biphasic half life, initial half-life of 24 hours, terminal half life of 15 days. Adverse effects ○ Causes some degree of renal toxicity in 80% of people who receive it ○ Toxicity reduced GFR and contributes to hypo-K and hypo-Mg, accumulation of creatine and urea in blood (azotemia) ○ Lipid formulations cause less renal toxicity and should be used in people with renal impairment and those who are intolerant of traditional formulation Nystatin ○ Active against Candida spp. ○ Topical formulations including crm, oint, and powders for mucocutaneous candidiasis ○ PO tablets and suspensions for intestinal candidiasis ○ Vaginal tablets for vulvovaginal candidiasis Amphotericin B ○ Route → topical, IV, intrathetcal, intraventricular ○ Oral bioavailability → N/A ○ Elimination ½ life → 24 hours or 15d ○ Route of elimination → Renal excretion Nystatin ○ Route → PO, topical ○ Oral bioavailability → N/A ○ Elimination ½ life → N/A ○ Route of elim → N/A Natamycin ○ Route → ocular ○ Oral bioavailability → N/A  ○ Elimination ½ life → N/A ○ Route of elimination → N/A Azole derivatives Diazole compounds ○ Clotrimazole aka Lotrimin ○ Econazole ○ Ketoconazole aka Nizoral Triazole compounds ○ Fluconazole aka Diflucan ○ Itraconazole aka Sporanox ○ Posaconazole aka Noxafil ○ Voriconazole aka Vfend Kinetics ○ Most are well absorbed from gut with exception of posaconazole ○ Absorption of ketoconazole, itraconazole and posaconazole required gastric acid, so acid-reducing drugs should not be given concurrently ○ Widely distributed to tissues and body fluids, but only fluconazole achieves significant concentration in CSF ○ Undergo hepatic biotrans, compounds excreted in urine and feces Adverse effects ○ Usually well tolerated but systemic administration can cause skin rash, elevated LFTs, hepatic injury, hematopoietic toxicity or GI distress (N/V/D) ○ Inhibit CYP3A4, so concurrent use with other drugs can cause interactions ○ Chronic use of fluconazole in high doses showed increase risk of birth defects Itraconazole and fluconazole ○ Itraconazole aka Sporanox particularly useful in the treatment of blastomycosis and histoplasmosis, and is widely used to treat onychomycosis ○ Fluconazole aka Diflucan penetrates CSF, used to prevent cryptococcal meningitis in patient with AIDS; also used for follow up after patient cryptococcal meningitis finish amphotericin B ○ Fluconazole also used to treat mucocutaneous and disseminated candidiasis, also candidal UTIs and vaginal candidiasis Ketoconazole aka Nizoral ○ Available in PO and topical formulations (including shampoo) ○ Oral formation is less widely used than itraconazole or fluconazole because it has a greater potential for drug interactions ○ Doesn’t penetrate CSF and has lower activity against other fungi ○ Topical formulations are useful for treating seborrheic dermatitis and tinea infections Clotrimazole  ○ Route →topical ○ Oral bioavailability → N/A ○ Elimination ½ life → N/A ○ Route of elimination → N/A Econazole ○ Route →topical ○ Oral bioavailability → N/A ○ Elimination ½ life → N/A ○ Route of elimination → N/A Fluconazole ○ Route → PO, IV ○ Oral bioavailability → 95% ○ Elimination ½ life →35 hr ○ Route of elimination → renal Itraconazole ○ Route →PO ○ Oral bioavailability → 95% ○ Elimination ½ life → 60 hr ○ Route of elimination → renal, biliary, fecal Ketoconazole ○ Route → PO, topical ○ Oral bioavailability →varies ○ Elimination ½ life → 8 hr ○ Route of elimination → biliary, fecal Posaconazole ○ Route → PO ○ Oral bioavailability → varies ○ Elimination ½ life → 28 hr ○ Route of elimination → fecal Voriconazole ○ Route → PO, IV ○ Oral bioavailability → 96% ○ Elimination ½ life → dose-dependent ○ Route of elimination → renal Echinocandin Drugs Caspofungin aka Cancidas ○ First echinocandin drug to be approved in the US ○ Excellent activity against Candida spp., good overage of aspergillus spp. ○ Covers candida strains that are resistant to azole compounds ○ Very effective in treating esophageal, oropharyngeal and invasive candidiasis Other Antifungals Flucytosine ○ Used orally to treat severe fungal infections ○ Gets converted to 5-FU inside fungal cells, gets incorporated into fungal RNA, and interferes with protein synthesis ○ Human cells don’t activate the drug Griseofulvin ○ Fungistatic antibiotic derived from penicillium griseofulvum ○ Active against many dermatophytes but not against Candida or other fungi ○ Standard treatment for tinea capitis ○ Kinetics Lipophilic drug, not very soluble in water so absorption is increased when taken with a high-fat meal Drug gets deposited in keratin precursor cells of skin, hair and nails Infected cells are exfoliated and replaced by non-infected tissue Metabolized in liver, excreted in urine Ciclopirox Tolnaftate