6, 9/22 antifungal therapies

exam 2, lesson 39

What is fungi

kingdom of living organisms that include molds, yeasts, and mushrooms

What is unique about fungi

cannot make their own food

absorb nutrients from toher organic material

often grow in dark, damp environments

what describes antifungal therapy

often long term, fungistatic, associated with toxicity

expensive

influenced by host immunity

what kind of therapy do immunocompromised hosts require

fungicidal

what is a consideration for cats

they metabolize drugs differently (azole sensitivity)

What should be considered when choosing antifungal therapy

spectrum of activity

site of infection

patient factors

drug safety and toxicity

drug-drug interactions

what is the fungal cell walls

chitin and B-1,3-glucan

targeted by echinocandins- inhibit b-glucan synthesis

what does the fungal cell membrane contain

ergosterol instead of cholesterol

what are the 3 main cell membrane drug targets

polyenes (amphotericin B)

azoles

allyamines (terbinafine)

what do polyenes target

bind ergosterol-pore formation-cell death

what do azoles target

inhibit ergosterol synthesis (12-a-demethylase)

what do allyamines target

inhibit squalene epoxidase- blocks ergosterol production

what is a broad spectrum antifungal drug

Ketoconazole (nizoral)

What are 3 narrow spectrum antifungals

Nystatin: candida, malassezia (yeast) only

Griseofulvin: orally for ringworm

Amphotericin B (toxic) last choice, only systemic

what drugs are topical use only

miconazole

enilconazole

coltrimazole

nystatin

natamycin

what drugs are for systemic use only

griseofulvine

wnhat drugs can be used for topical or systemic use

terbinafine

ketoconazole

fluconazole

itraconazole

amphotericin B

What are 2 examples of a polyene drug

amphotericin B and nystatin

What is the mechanism of polyene

bind ergosterol-pore formation-fungal cell death

what are the key issues of poleyene drugs

nephrotoxicity for amphotericin B, IV administration (except nystatin topical/oral)

what is the clinical use of polyene drugs

severe systemic infections (cryptococcosis and blastomycosis)

what are the adverse effects of polyene drugs

phlebitis, fever, nausea, vomiting, and cardia arrhythmias in dogs

what is an example of an allyamine

terbinafine

what is the mechanism of allyamines

inhibits squalene epoxidase-ergosterol depletion

when are allaymines used

dermatophysosis, some systemic infections

what is an advantage of allyamines

often well tolerated, High Vd

what are some adverse affects of allyamines/terbinafine

mild effects on the liver

when combines with azoles, cats facial dermatitis and pruritus

what does griseofulvine work against

organisms causing sermatophytosis (microsporum, trichophytan, and epidermophyton)

what are the pharmacokinetics of griseofulvine

drug distributes to skin, nails and hairs, only a fraction goes to other organs

metabolised in the liver with enterohepatic recycling

what are the adverse effects of griseofulvine

mostly in cats, leuopenia, anemia, neurotoxicosis

teratogenicity in cats, dogs, and livestock- avoid pregnant animals

not for horses with impaired liver function

what are some examples of azoles

imidazole: ketoconazole and clotrimazole

triazoles: fluconazole, itraconazole, and voriconzaole

what is the mechanism of azoles

inhibit ergosterol synthesis (CYP450 inhibition)

What is the spectrum of azole use

broad, mostly fungistatic

hepatotoxicity risk

What are the clinical uses for azoles

dermatophytosis (itraconazole)

cryptococcosis: (fucanzoles- good CNS penetration)

histoplasmosis/blastomycosis: itraconazole first line

what are the pharmacokinetics of azoles

high Vd, good oral bioavailability, some require acidic pH

liver metabolism and elimination with bile

What are the adverse effects of azoles

GI disturbances in some cases

ketozonazole can case severe

iraconazole can cause kidney issues long term

what are the mechanisms of antifungal resistance

altered ergosterol synthesis

efflux pumps

biofilm formation

cell wall modification

tarhet alterations

what are emerging concerns for antifungal resistance

Candida

aspergillus