Pharmacology - Antifungals Flashcards
Why is antifungal drug treatment often more prolonged than antibacterial treatment?
fungal organisms grow more slowly; drugs used (primarily azoles) are fungistatic not fungicidal
Mechanism of action of azole antifungals?
Inhibit sterol 14alpha-demethylase, a cytochrome p450-dependent fungal enzyme involved in synthesis of ergosterol (component of fungal cell wall) from lanoesterol –> result is accumulation of 14alpha-methylsterols, which disrupt the fungal cell membrane
Mechanism of action: echinocandins
disrupt function of the (1–>3)-beta-D-glucan synthase complex; inhibit the formation of beta-1,3-D-glucans in the fungal cell wall
What are the components of the fungal cell wall?
interwoven polymers of glucans, chitins, and various proteins
Mechanism of action: amphotericin B
forms aggregates in cell membrane with ergosterol, leading to pores that cause leakage of cellular contents
Mechanism of action: 5-flucytosine
disrupts RNA (via 5-fluorouridine triphosphate) and DNA (via 5-flurodeoxyuridine monophosphate) synthesis
T/F: All azole antifungals are teratogenic.
True - should be avoided in pregnancy
What is the difference between imidazoles or triazoles?
imidazoles contain 2 nitrogen molecules in their azole ring; triazoles contain 3 nitrogen molecules in their azole ring
What are the imidazole antifungal drugs?
ketoconazole, enilconazole, clotrimazole
Route of adminstration: enilconazole
topical – poor oral bioavailability
Route of adminstration: clotrimazole
topical – poor oral bioavailability
Route of adminstration: ketoconazole
both oral and topical
What are the triazole antifungal drugs?
itraconazole, fluconazole
Difference in metabolism between imidazoles and triazoles?
triazole antifungals are more slowly metabolized and have less impact on mammalian sterol synthesis than imidazoles
Mechanism of resistance to azole antifungals?
mutations in the gene encoding the demethylase enzyme, increased production of C-14alpha demethylase, and increased azole efflux by fungal cell membrane transporters
T/F: Resistance to one azole implies resistance to other azole antifungal drugs.
FALSE
Primary indications for ketoconazole
Malassezia dermatitis, feline nasal and cutaneous cryptococcosis
What improves oral absorption of ketoconazole?
administration with food
What inhibits oral absorption of ketoconazole?
antacids
How is ketoconazole metabolized?
liver (BUT moderate hepatic dysfunction does not alter blood levels of ketoconazole)
How is ketoconazole excreted?
inactive products are excreted in bile, and to a lesser extent, the urine
T/F: Ketoconazole is ineffective for treatment of meningeal cryptococcosis.
True - poor CNS penetration
Tissue distribution: ketoconazole
skin, bone, joint, lung – poor CNS penetration
Spectrum of activity: ketoconazole
dimorphic fungi, Malassezia; ineffective for aspergillosis
Tissue distribution: itraconazole
skin, bone, lung; may enter the CNS and eye with inflammation
Spectrum of activity: itraconazole
dimorphic fungi and molds, Malassezia
Tissue distribution: fluconazole
widely distributed - skin, lung, CNS, urine, eye
Spectrum of activity: fluconazole
Some Candida spp. Malassezia spp., some dimorphic fungi; Poor activity against molds. Aspergillus spp. are intrinsically resistant
Spectrum of activity: voriconazole
Dimorphic fungi, yeasts, and molds with the exception of Sporothrix schenckii and zygomycetes
Tissue distribution: voriconazole
CNS, eye, lung, bone
Spectrum of activity: posaconazole
Dimorphic fungi, yeasts, and molds INCLUDING zygomycetes
Tissue distribution: posaconazole
Widely distributed
Spectrum of activity: Amphotericin B
Broad spectrum. Also active against Leishmania
Tissue distribution: Amphotericin B
Limited penetration of CNS and eye
Spectrum of activity: 5-Flucytosine
Cryptococcus and Candida spp.
Tissue distribution: 5-Flucytosine
widely distributed - including CNS, urine, eye
Spectrum of activity: griseofulvin
dermatophytes
Tissue distribution: griseofulvin
concentrates in the skin
Spectrum of activity: terbinafine
activity highest for dermatophytes. To a lesser extent may have activity against other dimorphic and filamentous fungi
Tissue distribution: terbinafine
concentrates in the skin and hair
Spectrum of activity: capsofungin
Candida and Aspergillus spp. NOT active against Cryptococcus spp. OR when given alone to treat Coccidioides
Tissue distribution: capsofungin
widely distributed - poor penetration of CNS and eye
Adverse effects: ketoconazole
vomiting, anorexia, lethargy, diarrhea, increases of serum transaminases; hepatitis; pruritus and cutaneous erythema; lightening of hair coat color and cataract formation
Why are drug-drug interactions common with ketoconazole?
potent inhibitor of mammalian cytochrome p450 enzymes and efflux transporter proteins such as P-glycoprotein; inhibits testosterone and cortisol synthesis
What improves oral absorption of itraconazole?
best absorbed when given with food - because the acid secretion stimulated with feeding increases the drug solubility (necessary for dissolution and absorption)
What is itraconazole complexed with to improve solubility?
cyclodextrin
What inhibits oral absorption of itraconazole?
gastric acid suppressants (H2 blockers, PPI)
What is the only triazole drug that is converted to an active metabolite? What is the metabolite?
itraconazole –> hydroxylitraconazole
T/F: Advanced liver disease decreases itraconazole concentrations.
False - INCREASES itraconazole concentrations
Adverse effects: itraconazole
vomiting and anorexia; hepatotoxicity; ulcerative skin lesions (dogs given >10 mg/kg/day)
T/F: Both ketoconazole and itraconazole suppress adrenal and testicular function.
False - only ketoconazole does
What fungi are intrinsically resistant to fluconazole?
Aspergillus spp. (also has poor activity against molds)
Why does fluconazole diffuse into body fluids better than other azoles?
more water soluble
How is fluconazole excreted?
renal excretion account for more than 90% of elimination of fluconazole
Voriconazole is related to what other azole?
second-generation triazole derived from fluconazole
Voriconazole is not active against what fungi?
Sporothrix spp. or zygomycetes
What inhibits oral absorption of voriconazole?
food
Adverse effects: voriconazole
reversible visual effects (photophobia, blurred vision), peripheral neuropathies, photosensitization
What is the most potent inhibitor of p450 enzymes of the TRIazoles?
voriconazole
Posaconazole is related to what other azole?
itraconazole analogue
What azole has the broadest spectrum?
posaconazole – includes zygomycetes
What improves oral absorption of posaconazole?
fatty food
What inhibits oral absorption of posaconazole?
gastric acid suppressants (H2 blockers, PPI)
What immunomodulatory effects does amphotericin B possess?
activates macrophages and enhances macrophage-killing capacity
Route of adminstration: Amphotericin B
poor aqueous solubility and is not absorbed from the GI tract - formulated for IV infusion
Adverse effects: Amphotericin B
nephrotoxicity**, fever, inappetance, vomiting, phlebitis at the IV infusion site
How can nephrotoxicity with Amphotericin B be decreased?
loading with sodium before the infusion, slow administratioin in a large volume of fluid
Why are lipid formulations of Amphotericin B less nephrotoxic?
reduced rate of transfer of AMB to mammalian cell membranes and increased drug clearance from the blood by the mononuclear phagocyte system
Why is mammalian cell toxicity limited with 5-Flucytosine?
mammalian cells cannot convert flucytosine into 5-fluorouracil
Why is 5-flucytosine given concurrently with Amphotericin B?
marked drug resistance can occur during treatment, flucytosine may be synergistic with AMB
Mechanism of resistance to 5-flucytosine?
modifications in fungal enzymes that are required for flucytosine uptake and metabolism
Route of adminstration: 5-flucytosine
oral - absorbed rapidly and well from GI tract
How is 5-flucytosine excreted?
80% of the dose is excreted unchanged in the urine
Administration of 5-flucytosine is contraindicated in what species?
dogs – often develop a severe drug eruption (TEN) within 2-3 weeks of starting treatment
Adverse effects: 5-flucytosine
myelosuppression and GI signs
Mechanism of action: griseofulvin
binds to fungal tubulin – leading to impaired microtubule function and mitotic arrest
Is griseofulvin fungicidal or fungistatic?
fungistatic
What improves oral absorption of griseofulvin?
fatty food or whole milk
What effect does griseofulvin have on cytochrome p450 enzymes?
INDUCES cytochrome p450 enzymes – decreases efficacy of drugs that are metabolized to inactive metabolites by P450 enzymes
Adverse effects: griseofulvin
drug-drug interactions (induces cytochrome p450), teratogenic, inappetance, vomiting, diarrhea; myelosuppresion in cats (esp with FIV infection)
Mechanism of action: terbinafine
synthetic allylamine that inhibits fungal squalene epoxidase – blocks fungal lanosterol and ergosterol synthesis –> leads to accumulation of toxic squalene –> fungal cell lysis
Mechanism of resistance to terbinafine?
altered squalene epoxidase
What improves oral absorption of terbinafine?
administration with food
Is capsofungin fungicidal or fungistatic?
fungicidal against Candida spp. and fungistatic against Aspergillus spp.
Why are echinocandins ineffective against Cryptococcus?
because they possess little glucan synthase
Route of adminstration: caspofungin
IV infusion
