Antifungals Flashcards
Fungus is considered a ___ organisms
eukaryotic
Why are anti fungal drugs so dangerous?
- the drug goes systemic - are life threatening
What is the cell wall of fungus made up of?
- made up of chitin, which is a polymer of N-acetylglucosamine
What does the cell membrane of fungus contain?
ergosterol
What are 2 of the things that increases the incidence of fungal infections?
- suppressed IS linked to increase in incidence
- long term antibiotic tx
What class of drugs does Amphotericin B fall into?
- polyene macrolide
(produced by streptomycin nodosus) - used only for life threatening disease
How does amphotericin B work to treat a fungal infection?
- binds to ergosterol (not cholesterol) in the cell membrane and forms pores
What fungi does amphotericin B act on?
- acts on a wide range of fungi, including Candida and blastomyces, as well as aspergillus and protozoa
- is the first line tx when substituted
What is the absorption of amphotericin B? How does that effect how its dosed?
- poorly absorbed in the GI tract- given intravenously
- insoluble in water
- given intrathecally for meningitis
- delivered now in liposomes- lowers the toxicity
What are the adverse effects associated with amphotericin B?
- has a low TI, so it is NOT considered a safe drug
- dose has to be under 1.5 mg/kg
- anaphylaxis and convulsions
- fever
- hypotension
If given longer term - renal impairment
- anemia
- neurological effects
- thrombophlebitis (blood clot formation)
What is the action of flucytosine in the fungal cell?
- synthetic pyrimidine antimetabolite
- enters via specific cytosine permease- not in mammals
- converted to 5’-fluorodeoxyuridine monophosphate (5-FdUMP)
- false nucleotide inhibits thymidylate synthase
- blocks thymidylic acid- needed for DNA
There is ____ when flucytosine and amphotericin B are combined
synergy
How does resistance develop when using flucytosine?
- target enzyme can be down regulated- there is a need for combination therapy here
How does flucytosine pass into the BBB?
passes very well into the BBB
What are the adverse effects related to flucytosine?
adverse effects are related to the toxic metabolite fluorouracil
- neutropenia
- bone marrow depression
- nausea, vomiting
- contraindicated with renal impairment
What class of anti fungal does posaconazole belong to and how does it work?
- synthetic azole used for a SYSTEMIC fungal infection
- inhibits C-14 alpha-demethylase (cyt P450)
- blocks demethylation and lanosterol to ergosterol, therefore disrupting the membrane structure and function
- more specific than precious axle and imidazoles
What is the range of fungi that posaconazole can treat?
- species of Candida and Aspergillus
How is posaconazole dosed and absorbed in the body?
- orally dosed- gastric acid is needed for release
- there is major binding to plasma proteins
- drug is metabolized in the liver
- poor CNS penetration
What are the adverse effects associated with posaconazole?
- minor GI upset
What drug interactions are associated with posaconazole?
- inhibition of cyt P450
How does caspofungin work to treat fungal infections?
- inhibits beta-(1,3)-D-glycan
- causes cell wall disruption and death
- treats both aspergillus and candida
- used as second linetx
What is terbinafine used to treat and how does it work?
- terbinafine inhibits squalene epoxidase and blocks ergosterol
- (squalene build-up can be toxic, however)
- used to treat cutaneous dermatophyte infections
Why is treating protozoa so difficult?
- the metabolism of protozoa is very close to that of humans
- there is a big issue with toxicity, esp against metabolically active cells such as neurons and stem cells
- pregnant patients cannot be treated for this reason
What is amebic dysentery caused by and what are the symptoms?
- caused by entamoeba histolytica
- anaerobic protozoa
- causes fulminating diarrhea
- liver abscess
- can lie dormant
- ultimately ulcerate the host intestine and feed off an kill the host bacteria
What organism is metronidazole used to kill?
- kills E. histolytica trophozites
Anaerobic protozoa have ____ low redox potential electron transport proteins- nitro group of metronidazole acts as an electron acceptor. The subsequent reduced compounds are cytotoxic
ferridoxin like
What are the adverse effects of metronidazole?
GI adverse effects
What are luminal amebicides used for?
- should apply after systemic treatment
- asymtomatic colonization within the intestine
- Iodoquinol is used - cyst and trophozoite forms
What is systemic amebicides used for?
- useful for liver abscess or intestinal wall infection
- chloroquine
What parasite is malaria caused by?
by plasmodium protozoa parasites (plasmodium falciparum and plasmodium vivax)
- passed by the infective anopheles mosquito
What are some of the effects of malaria?
- high fever
- orthostatic hypotension
- erythrocytosis
- capillary obstruction
- anemia
- raised intracranial pressure
What is the life cycle of malaria?
- starts off with sporozoites
- infects the liver within 30 minutes
- dormant hypnozoites
- invisible to the immune system
- form a schizont
- merozoites infect the blood cells
Describe the action of primaquine
- primary and secondary exoerythrocytic forms - mainly found in the liver
- kills all gametocytic forms
- does not affect erythrocytic form - use is combined with the blood schizonticide
- metabolites of primaquine induce oxidative stress
- well absorbed- oral
- drug induced hemolytic anemia in patients with low G6PDH
- contraindicated during pregnancy
Describe the action of chloroquine
- mainstay of antimalarial therapy
- blood schizonticide - erythrocytic form
- effective against systemic amebiosis
Chloroquine has ____ dosing, is ____ absorbed in only 4 days of therapy, and has a ___ volume of distribution
- oral
- rapidly
- large
What cells does chloroquine persist in?
- erythrocytes
Why should chloroquine not be used in pregnancy
cross the BBB and placenta
