Antifungals Flashcards
(42 cards)
Amphotericin B
Large molecules with hydroxylated portion that is hydrophilic and a portion containing 4-7 double bond which is lipophilic, Effective but toxic
Amphotericin B Spectrum of Action
Drug of choice for life-threatening fungal infection, Choice for empiric therapy of suspected fungal infection in neutropenic patients, Available as ointment or non absorbable oral forms for non-systemic candida infections
Amphotericin B Mechanism of Action
Binds to sterols (Ergosterol) in cell membranes, Forms pores or channels that alter fungal cell membrane permeability and cause leakage of essential cell components leading to death; Fungicidal or Fungistatic depending on conc. of ergosterol in membrane
Amphotericin B Pharmacokinetics
Poorly absorbed from GI tract so not given orally, Insoluble in water so prepared as colloidal dispersion with sodium deoxycholate, SUV, ABCD to, Excreted in urine
Amphotericin B Drug Interactions
Synergistic with Flucytosine, Antagonistic with Imidazoles - Inhibit synthesis of sterol
Amphotericin B Adverse Effects
Rapid infusion produces cardiotoxicity, Amph B causes release of TNF-alpha and IL-1 from host immune cells leading to chills, fever, rigors, hypotension, headache; Nephrotoxic, vasoconstrict renal artery, leading to renal ischemia, Anemia due to inhibition of erythropoietin production rather than suppressing bone marrow
Amphotericin B Resistance
Decreased amount of, or complete lack of ergosterol in cell membranes, Elevated levels of ergosterol precursor in membranes
Nystatin
Effective but systemic toxicity, Polyene macrolide anti fungal agent
Nystatin Uses
Polyene anti fungal used topically/enterally (not absorbed from gut), Systemic toxicity, Choice for candidial infection of oral cavity (Oral monoliasis, thrush, denture stomatitis), Topical and oral forms of nystatin are not absorbed on ingestion and consequently are not associate with drug-drug interactions, HIV/AIDS with low CD4 count - Patients undergoing chemotherapy and patient whom azole anti-fungals contraindicated.
Prescription
Oral suspension for oral candidiasis - 100,000units/mL - - 480mL (1pint) bottle - Swish then swallow 2tsp qid for 14days; Cream - 100,000units/g, 30g tube, Apply 4-5times/day for 2 weeks
Flucytosine Chemistry
Antifungal Agent; Fluorinated pyrimidine related to Fluorouracil blocks synthesis of RNA
Flucytosine Spectrum of Action
Active VS Candia, Toralopsis and Cryptococcus, Fungistatic VS Aspergillus fumigatus (chromomycosis), Combined with amphotericin B for cryptococcal meningitis in AIDS patients
Azoles Chemistry
Antifungal Agent;
Imidazoles - 2N in Azole ring - Clotrimazole (Oral candidiasis in form of troche), Miconazole, Ketoconazole (Nizoral - mucocutaneous candidiasis)
Triazoles - 3N in Azole ring - Fluconazole (Systemic candidiasis), Itraconazole, Voriconazole, Efinaconazole (Jublia)
Azoles Mechanism of Action
Antifungal Agent; Inhibit synthesis of ergosterol by inhibiting sterol 14-alpha-demethylase, a cytochrome P450 dependent enzyme system that converts lanosterol to ergosterol
Azoles Spectrum of Action
Broad spectrum including Dermatophytes (Microsporum, Trichophyton, Epidermophyton), Yeasts (Cryptococcus Neoformans, Candida, Torulopsis Glabrata), Dimorphic Fungi (Coccidioides Immitis, Histoplasma Capsulatum, Blastomyces Dermatidis, Paracoccidioides)
Ketoconazole Uses
Useful for vulvovaginitis, Oral and esophageal candidiasis, Mucocutaneous candidiasis, Available as cream and lotions for common skin fungi, Ketoconazole used to inhibit androgen production in cases of advanced prostate cancer, Inhibit corticosteroid synthesis in cases of advanced adrenal cancer
Ketoconazole Drug Interactions
Inhibit hepatic P450 enzymes causing drug interactions, Inhibit P450 enzymes 17,20 lyase (desmolase) and side-chain cleavage enzyme in adrenal glands and gonads thereby decrease steroid hormone biosynthesis, High dose Ketoconazole inhibit androgen synthesis to cause gynecomastia and impotence - Menstrual irregularity due to decrease steroid biosynthesis
Ketoconazole Pharmacokinetics
Available in both oral and topical forms, Ketoconazole is well absorbed from GI tract - need acidic environment for dissolution, Little penetration into CSF in absence of disease, Ketoconazole is extensively bound to plasma proteins (Albumin), Unbound drug distributes to most tissue, Ketoconazole is extensively metabolized in liver by O-dealkylation and aromatic hydroxylation to inactive metabolites, Inhibit CYP3A4, 2C9, 2C19, UGTA1, UGT2B7, P-glycoprotein
Ketoconazole Adverse Effects
Ketoconazole causes GI ulceration with nausea, dizziness, pruritus, headache, Hepatotoxicity and increase in liver enzymes in plasma - Fatal hepatic necrosis may occur (Hepatic failure), N, V, D abdominal pain, Reversible alopecia w/prolonged oral therapy, Rare cases of Stevens Johnson syndrome, Inhibit androgen production, Inhibit corticosteroid synthesis
Ketoconazole Drug Interactions
Bioavailability decreased by antacids or drugs that inhibit acid production, Antacids and vitamin supplements chelate ketoconazole and impair absorption, GI absorption depend on acid conversion to salt in stomach so does not work if patient take bicarbonate, antacid, H2 blockers, proton pump inhibitors, achlorhydria
Ketoconazole (Nizoral) Dosing
Normal dose - 200/400mg q24h, No dose alter ate needed with kidney disease, 50% reduction with liver disease
Fluconazole
Diflucan;
Drug of choice to treat systemic candidiasis, cryptococcal meningitis, coccidioidal meningitis, not effective VS aspergillosis
Fluconazole Pharmacokinetics
Most widely used anti fungal drug, Available as both oral and IV, Almost bioavailable and absorption is not affected by gastric pH, Diffuses freely into CSF, sputum, urine and saliva, excreted mainly by kidney
Fluconazole Mechanism of Resistance
Candida most readily develop resistance, Mutation of fungal P450, Overexpression of multi drug efflux transporter proteins
