Antifungal Drugs Flashcards
What are the azoles?
clotrimazole, fluconazole, itraconazole, ketoconazole, miconazole, posaconazole, voriconazole
What are the echinocandins?
anidulafungin, caspofungin, micafungin
What are the polyene macrolides?
amphotericin B, natamycin, nystatin
What are the allylamines?
naftifine, terbinafine, tolnaftate
What is the “other” antifungal drug?
flucytosine
What is mycoses?
an infectious disease caused by fungi
What are the most common locations of fungi infection?
skin, mucous membranes, hair, nails
Can there be deep fungal infections?
yes, can spread to blood and organs and be life threatening and difficult to treat
T/F Antifungals are only topical
false, they are systemic or topical
What are the characteristics of fungi?
eukaryote with rigid cell wall composed of chitin NOT peptidoglycan, cell membrane contains ergosterol, can exist in yeast or mold form
T/F fungi are usually resistant to antibiotics and bacteria are usually resistant to antifungals
true
Why is the incidence of fungal infections on the rise?
more organ transplants (with chronic immune suppression), chemotherapy, HIV, antibiotic treatment
What are azoles good for?
wide clinical use but good for superficial infections like candida and dermatophytes
What is the MOA of azoles?
inhibits enzyme responsible for converting lanosterol to ergosterol (disrupts fungal cell membrane structure and function)
What is the secondary MOA of azoles?
inhibit human gonadal and adrenal steroid synthesis leading to decreased testosterone and cortisol production
What are the adverse effects of azoles?
allergies and minor GI disturbances
What are the drug interactions of azoles?
inhibits CYP450 (potentiates toxicities of other drugs), decreased absorption when co-administered with agent decreasing gastric activity
What should azoles not be combined with?
amphotericin B because it needs ergosterol in the membrane
What shortens the duration of action of ketoconazole?
rifampin because it is an inducer of CYP450
What is ketoconzaole?
the first azole used, limited to topical, less selective for fungal enzyme=more side effects
What is true of fluconazole?
high oral availability and penetration to CNS
What is itraconazole?
drug of choice for histoplasmosis (not exactly fungus), administered orally or parenterally
What is the bioavailability of voriconazole?
96% bioavailability, oral or parenteral administration
T/F coriconazole is an extensive CYP450 inhibitor?
true, dose reduction may be needed for other meds
What are the adverse effects of voriconazole?
30% of patients report visual disturbances (blur, changes in color/brightness, occur immediately then resolve) photosensitivity dermatitis also common
What is posaconazole?
new oral/parenteral, broadest spectrum, developed to prevent infections in immunocompromised patients
Does posaconazole inhibit or induce CYP450?
inhibits some enzymes
Which three azoles are most common topically?
clotrimoazole, miconazole, and ketoconazole (shampoo too)
What is the MOA of echinocandins?
interferes with synthesis of B-glucan which disrupts fungal cell wall and causes lysis and cell death
What is the absorption of echinocandins?
IV only, poor oral absorption
What is caspofungin?
the second line if failure of amphotericin B or azole, requires dose adjustment if given with CYP450 inducer
What are the adverse effects of echinocandins?
well tolerated with few side effects, infrequent GI problems, flushing which may be histamine mediated
What is amphotericin B?
the only antifungal for years, high toxic potential but still drug of choice for life-threatening systemic mycoses
What is the MOA of amphotericin B?
binds to ergosterol in plasma membrane and forms a pore allowing electrolytes and small molecules to escape causing cell death
What is resistance of amphotericin B related to?
decreased ergosterol content of fungal membranes
What are the pharmacokinetic considerations of amphotericin B?
mainly given by slow IV infusion, extensively bound to plasma proteins, kidney and liver elimination
What are the adverse effects of amphotericin B?
low therapeutic index, infusion related toxicity, cumulative toxicity
What are the infusion related toxicity aspects of amphotericin B?
fever/chills, muscle spasm, vomiting, headache, hypotension
What is the cumulative toxicity aspect of amphotericin B?
renal impairment from decreased glomerular filtration rate (reversible) and anemia
What are nystatin and natamycin?
antifungals restricted to topical treatment of candida or corneal infections that resemble amphotericin B
What is the MOA of nystatin and natamycin?
binds ergosterol in plasma membrane and forms a pore
What is the only commercially available ophthalmic anti-fungal medication?
natamycin
What is available for the treatment of thrush?
oral mouthwash of nystatin or natamycin
What is flucytosine?
developed as anti-cancer with no real effectivity, now a antifungal
What is the MOA of flucytosine?
enters fungal cell and disrupts DNA/protein synthesis, converted intracellularly into 5FU an antimetabolite
What is resistance to flucytosine caused by?
decreased levels of enzymes used to convert 5FC to 5FU, rate is lower if given with additional antifungal
What is flucytosine often combined with?
amphotericin B, enters pores easily
What are the pharmacokinetics of flucytosine?
only available as oral drug, excretion via glomerular filtration, can penetrate CNS
What are the adverse effects of flucytosine?
neutropenia, thrombocytopenia, bone marrow depression, GI disturbances
What is the MOA of allylamines?
inhibits enzyme (squalene epoxidase) that converts squalene to lanosterol (aka blocks biosynthesis of ergosterol) –squalene builds up and becomes toxic
Which allylamine is topical and oral?
terbinafine
Which allylamine is topical only?
naftifine
What is the drug of choice for treating fungal infections of nails?
terbinafine (effective for skin infection as well)
What are the pharmacokinetics of allylamines?
40% bioavailability orally, deposited in skin, nails and fat, urinary excretion
What are the adverse effects of allylamines?
orally– GI disturbance, headache, rash, some visual disturbances
topically– irritation and redness when in contact with mucous membranes
