Antifungals agents Flashcards
two funguses transmitted from person to person
1.)ringworm of the scalp
2.) thrush in the newborn, resulting from infection
transmitted from the mother with Candida albicans during childbirth.
Dermatomycoses
Tolnaftate (Tinactin®).
Clotrimazole (Lotrimin®)
Griseofulvin
Tolnaftate MOA
inhibits fungal squalene epoxidase, resulting in decreased ergosterol biosynthesis in susceptible fungi
-inhibition of ergosterol biosynthesis results in selective cytotoxicity for the parasite and not the host
what is the selective toxicity for squalene epoxidase in fungi than humans?
fungal enzyme is more sensitive to the drug than the mammalian enzyme
Other squalene epoxidase inhibitors
terbinafine
naftifine
butenafine
Clotrimazole MOA
-azole class of antifungal agents
-azoles inhibit cytochrome P450, which catalyzes the 14α-demethylation of lanosterol during its conversion to
ergosterol
-in presence of azoles: inhibits the binding and activation of molecular oxygen by cytochrome P450 and therefore inhibits the conversion of lanosterol to ergosterol
selectivity of azoles
Azoles have greater affinity for the fungal cytochrome P450 than human cytochrome P450. However, selectivity is not absolute
-azoles can bind to human cytochrome P450 and inhibit drug metabolism
other azole drugs
Miconazole
Ketoconazole
Griseofulvin MOA
disrupts the mitotic spindle by binding to polymerized microtubules to inhibit mitosis
Griseofulvin used to treat
onychomycosis (fungal infection of nails)
-It is deposited in newly formed keratin, where it prevents fungal growth
characteristics of Griseofulvin
water insoluble, and the dissolution rate is very slow in water. Microsize and ultramicrosize particles are used to increase the dissolution rate. It is also taken with a high fat
diet to increase absorption.
side effects of Griseofulvin
photosensitivity, hypersensitivity, and headache
Antifungals to Treat Systemic Infections
Amphotericin B (Fungizone®) 5-Fluorocytosine (Ancobon®, Flucytosine) Ketoconazole (Nizoral®). Fluconazole (Diflucan®) Itraconazole Echinocandins
Amphotericin B MOA
involves binding to ergosterol in the membranes of sensitive fungi.
-Pores open in the membrane, allowing leakage of ions and small organic molecules
Amphotericin selectivity
binds 10 times more strongly to vesicles containing ergosterol than to those containing cholesterol.
-some does bind resulting in toxicity
Amphotericin characteristics
- amphoteric - it has both an acidic and a basic group.
- lipophilic polyene region (bottom) and a hydrophilic polyalcohol region
- poor water solubility
- not absorbed well from the GI tract
how should Amphotericin be administered?
slowly by IV infusion
how else is Amphotericin available
- bile salt complex called the deoxycholate complex
- cholesterol complex as a sterile lyophilized form-> reconstitutes in sterile water
- liposomal Amphotericin B suspension for injection
side effects of Amphotericin
- fever and chills.
- headache, N&V,
- nephrotoxicity, and hypotension
- major limiting toxicities are nephrotoxicity and hypokalemia
therapeutic use of Amphotericin
-life-threatening fungal infections
-broad spectrum antimycotic used in the treatment of deep mycoses including aspergillosis, blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, and
mucormycosis
5-Fluorocytosine MOA
-in presence of 5-fluorouracil
Susceptible fungi convert 5-fluorocytosine to 5-fluorouracil, which is converted into 5-fluorodeoxyuridine monophosphate (5-fluoro-2’-deoxyuridylic acid)
-5-Fluorodeoxyuridine monophosphate inhibits thymidylate synthase, thus inhibiting DNA biosynthesis.
in the presence of 5-fluorouracil
elimination of F+ is impossible because fluorine is the most electronegative element.
- In addition, 5-fluorouracil is incorporated into RNA in place of uracil, since the van der Waals radius of fluorine (1.35 Å) is very close to that of hydrogen (1.20 Å). This leads to inhibition of protein synthesis. In this sense, 5-fluorouracil is functioning as an antimetabolite (the analog of an essential substrate that is accepted by the metabolic pathway but cannot itself support the life of the cell).
- Binds adenosine
5-Fluorouracil is in itself
anticancer agent in humans
selectivity of 5-Fluorouracil
Human cells have little or no cytosine deaminase activity
therapeutic use of 5-Fluorocytosine
-used in combination with
amphotericin B to treat systemic Candida infections and Cryptococcus neoformans meningitis.
It is well absorbed through the GI tract, has a low incidence of toxicity, and can penetrate into
the cerebrospinal fluid (CSF)
-Candida, Cryptococcus, Torulopsis glabrata (now called Candida glabrata), Cladosporium, and Aspergillus
resistance of 5-Flurorcytosine
can develop during therapy
why is 5-Flurorocystosine used with amphotericin B
used in combination with amphotericin B to kill resistant strains when they emerge
-also, amphotericin B increases permeability of fungal cells to enhance the uptake of 5-fluorocytosine
toxicity of 5-Fluorocystosine
- nausea, vomiting, diarrhea, rash, and enterocolitis
why should 5-Fluorocystosine be monitored in people with bone marrow depression?
depress bone marrow function, leading to leukopenia
and thrombocytopenia
why should those with renal impairment be monitored with 5-Flurorcytosine
eliminated by the kidneys
how can N&V be avoided with 5-Fluorocystosine
capsules are administered a few at a time over a 15 min period.
Ketoconazole
-effective in treatment of blastomycosis, histoplasmosis, coccidioidomycosis, and paracoccidioidomycosis
what is tolerated better than amphotericin B
Ketoconazole
Fluconazole
- triazole
- high bioavailability and penetrates well into the CSF
use for Fluconazole
meningitis caused by susceptible fungi
Fluconazole selectivity
increased selectivity for fungal vs. human cytochrome P450.
This diminishes the incidence of adverse effects and drug interactions
therapeutic use of Fluconazole
-administered by IV infusion to treat cryptococcal
meningitis in AIDS patients
- first drug of choice for prevention of relapse of cryptococcal meningitis in AIDS patients whose infection has been controlled by amphotericin B
-administered as a single oral dose (150 mg) for treatment of vaginal candidiasis.
toxicity with Fluconazole
Rare cases of hepatotoxicity, including fatalities, have been reported
-Patients with abnormal liver function tests should be monitored for symptoms of hepatotoxicity
Itraconazole characteristics
- racemic mixture of four diastereomers.
- triazole.
- more than 90% bound to serum proteins and is extensively bound in tissues
what is Itraxonazole not effective in treating
infections of CNS
therapeutic use of Itraxonazole
-nonmeningeal histoplasmosis
-treatment of AIDS patients with disseminated
histoplasmosis whose disease has stabilized during amphotericin B therapy
side effects of Itraxonazole
- well tolerated at 200 mg/day
- GI distress occasionally prevents use of 400 mg/day
- nausea and vomiting (10%), hypokalemia (9%), and rash (2%)
- Rare cases of severe hepatotoxicity have occurred, including liver failure and death.
what patients should not be give Itraxonazole
congestive heart failure patients
what is contraindicated with Itraxonazole
cisapride, pimozide, quinidine, and dofetilide
what can increase interactions with itraxonazole
Coadministration of itraconazole with drugs that are metabolized by cytochrome P450
Echinocandins MOA
echinocandins inhibit 1,3-β-glucan synthesis in the fungal cell walls by noncompetitive inhibition of 1,3-β-glucan synthase
echinocandin selectivity
for the fungus and not the host is that
mammalian cells lack 1,3-β-glucan synthase
therapeutic use of echinocandins
broad spectrum antifungal
-agents that have no cross-resistance with other antifungals and are synergistic with voriconazole and amphotericin B.
penicillins of antifungal world
echinocandins
administration of echinocandin
IV
adverse reactions of echinocandins
hepatotoxicity and sensitivity/allergic reactions
echinocandins
Caspofungin(Cancidas®)
Anidulafungin(Erixis®)
Micafungin(Mycamine®)
