Antifungal Drugs! PDF

Antifungal Medications NUR 331 Powerpoint created by: Dr. Janee Gelineau-vanWaes, Pharmacology Department, Creighton University School of Medicine  FUNGAL DISEASES Systemic Mycoses -involve various internal organs; difficult to treat;...

Antifungal Medications NUR 331 Powerpoint created by: Dr. Janee Gelineau-vanWaes, Pharmacology Department, Creighton University School of Medicine  FUNGAL DISEASES Systemic Mycoses -involve various internal organs; difficult to treat; toxic medications Superficial Mycoses (yeast) -involve skin, nails, or mucous membrane  SYSTEMIC FUNGAL INFECTIONS (1) OPPORTUNISTIC MYCOSES - Occur primarily in debilitated and/or immunocompromised patients (AIDS, leukemia, lymphoma) – Candida, Aspergillus, Cryptococcus, Phycomycetes (2) ENDEMIC MYCOSES (Non-opportunistic) - Caused by various pathogens distributed unevenly around the world, can occur in any host - Blastomycosis - Histoplasmosis - Coccidiomycosis – Valley Fever - Sporotrichosis ENDEMIC MYCOSES  2 Major Classes of Antifungal Drugs Polyene antibiotics (Amphotericin B, Nystatin) Azoles (Fluconazole, Itraconazole, Ketoconazole, Clotrimazole) Two other classes exist - Echinocandins and Pyrimidine analogs POLYENE ANTIFUNGAL AGENTS AMPHOTERICIN B - used to treat deep systemic mycoses - before Amphotericin B, most systemic infections were fatal NYSTATIN - useful in treatment superficial mycoses of candidiasis (skin, mouth, esophagus, vagina) POLYENE ANTIFUNGAL AGENTS MECHANISM OF ACTION → binds to ergosterol, a component of the fungal cell membrane → binding forms channels in the cell membrane, increasing its permeability → cells leak intracellular cations (Na+, K+, and H+ ions) *Resistance to polyenes is associated with replacement of ergosterol by other sterols in the fungal plasma membrane  CAUTION with Amphotericin B -Broad-spectrum antifungal agent; drug of choice for systemic mycoses -Highly toxic; fungistatic or fungicidal depending on pH, concentration, and fungus -Effective against some protozoa (Leishmania) -Infusion reaction and renal damage occur in ALL patients to varying degrees -Extent of kidney damage related to total dose (minimized by infusing additional normal saline) -Be careful with other nephrotoxic drugs!  AMPHOTERICIN B Administration -absorbed poorly from GI tract (oral therapy not effective) -administer by slow IV infusion over 2-6 hours every day or every other day for several months (3-4 months) -infusion reactions (fever, chills, rigors, nausea, headache) -symptoms begin 1-3 hours after start of infusion; less intense with lipid-based infusion; can give acetaminophen, diphenhydramine -hypokalemia from kidney damage; may need supplements -can cause bone marrow suppression  Azoles -broad spectrum synthetic compounds for treating systemic mycoses -less toxic than Amphotericin B -can be given orally -disadvantage: Inhibits P450 drug-metabolizing enzymes and can increase levels of other drugs Itraconazole (Sporanox) Newer broad-spectrum azoles valuable Fluconazole (Diflucan) for severe fungal infections in Ketoconazole (Nizoral) immunocompromised patients Mechanism of Action -inhibits enzyme involved in the synthesis of fungal ergosterol; inhibits cytochrome P450 enzymes increasing levels of other drugs Itraconazole (Sporanox)  -broader spectrum than most azoles  -well absorbed from GI when given with meals  -highly bound to plasma proteins (>99%)  -long half-life, ~20 hours after single dose  -mostly metabolized in the liver  -adverse reactions include cardiosuppression, hepatotoxicity, hypokalemia, hypertension FLUCONAZOLE – Therapeutic Uses (Diflucan) -well absorbed from the GI tract & distributed throughout body, including CNS -effective in immunocompromised patients -teatment of cryptococcal meningitis; blastomycosis, histoplasmosis -long half-life (20-50 hrs adults; 17 hrs children) -excreted largely unchanged in kidney -treatment of mucosal (oropharyngeal/esophageal) candidiasis -weekly prophylaxis against mucosal candidiasis in HIV/AIDS FLUCONAZOLE – Adverse Effects - GI disturbances - nausea, vomiting, gastric pain - Headaches - Rashes - Seizures - Anaphylaxis - Dermatitis *high doses during first trimester of pregnancy can cause birth defects  KETOCONAZOLE (Nizoral) - 1st oral antifungal approved for chronic systemic mycoses - well absorbed from GI if stomach content is acidic - generally well tolerated - antacids and H2 antihistamines markedly ↓ absorption  KETOCONAZOLE Toxicity - < toxic alternative to Amphotericin - Severe hepatotoxicity in approx. 0.01% of individuals - Markedly inhibits synthesis of testosterone and estradiol → gynecomastia → menstrual irregularities → alterations in adrenal steroid synthesis Common superficial mycoses (fungal infections) Tinea pedis – ringworm of the foot “athlete’s foot” Tinea corporis – ringworm of the body Tinea cruris – ringworm of the groin “jock itch” Tinea capitis – ringworm of the scalp Vulvovaginal candidiasis Oral Candidiasis (thrush) Onychomycosis (fungal infection of nails) Treated with topical and/or oral drugs  TOLNAFTATE – superficial mycoses -thiocarbamate commonly used as topical antifungal agent -superficial skin and nail infections (tinea pedis, tinea cruris, etc.) -generally ineffective against yeast (ie. Candida) -adverse effects involve allergic contact dermatitis, possibly teratogenic  NYSTATIN (Polyene) -not much absorption from skin, mucous membranes, or GI -used primarily to treat candidal infections of mucosa, skin, intestinal tract and vagina -topical Nystatin remains drug of choice for treatment of candidal infections of the oral cavity - Oral moniliasis - Thrush - Denture stomatitis  CLOTRIMAZOLE -Used for various mucosal and cutaneous infections -Spectrum and MOA similar to other azoles -Restricted to topical use (1% cream or lotion) -Preparation available specifically for intraoral use  MICONAZOLE - 1st azole approved for topical and parenteral use - no longer used systemically and specific formulation for intraoral use unavailable - 2% miconazole nitrate cream used for cutaneous and vaginal Candida albicans infections - may cause burning, redness, itching (Micatin, Monistat) RINGWORM Athlete’s Foot