Antifungals Flashcards
What type of molecule is Amphotericin B?
ampoteric polyene macrolide
Is Amphotericin B soluble in water?
no: it is nearly insoluble in water
What is Amphotericin B compounded with for IV injection?
sodium desoxycholate
Is AmpB absorbed well or poorly from the GI tract?
poorly
Can oral ampB be used for treatment of systemic disease?
No: oral only effective on fungi within the lumen of the GI tract
What percent of ampB is bound by serum proteins?
90%
How is ampB eliminated?
Mostly metabolized but some excreted slowly in the urine.
What is the serum half life of ampB?
15 days
Is dose adjustment required for a patient with hepatic impairment, renal impairment, or dialysis?
no
Where is ampB distributed in the body?
widely distributed to most tissues
Does ampB penetrate CSF well?
No: only 2-3%
Is ampB therapy limited by toxicity?
Yes
What’s the most concerning toxicity caused by ampB?
drug-induced renal impairment
Why is ampB packaged in a lipid formulation?
lower toxicity
How does the lipid formulation allow lower toxicity?
binds to mammalian membranes less readily
Do the lipid delivery vehicles serve as an ampB reservoir?
Yes, which reduces nonspecific binding to human cell membranes
List all of the advantages of liposomal ampB delivery?
reduction of toxicity w/o sacrifice of efficacy, permits use of larger dose, some fungi contain lipases that may liberate free ampB directly at site of infxn
What is ampB’s mechanism of action?
Binds to ergosterol and forms a pore in fungi cell membranes
How is ampB selective?
only binds to ergosterol and not cholesterol in human cell membranes
Which side of ampB binds lipids/ergosterols?
double bond rich side
Which side of ampB binds water?
hydroxyl rich side
Why is the amphipathic characteristic of ampB important?
facilitates pore formation (hydrophobic side on outside of pore and hydrophilic side lines canal of pore)
How does the formation of the pore lead to fungi cell death?
allows leakage of intracellular ions and macromolecules
What accounts for the toxicity of ampB?
some binding of human cholesterol does occur
When does ampB resistance occur?
when ergosterol binding is impaired
How do fungi confer resistance to ampB? 2 ways.
- decrease membrane concentration of ergosterol 2. modify binding site on ergosterol to decrease affinity
Does ampB have the broadest spectrum of action among all the antifungals?
yes
What limits ampB’s use clinically?
it’s toxicity: mainly used in life-threatening mycotic infxns (usually used initially to rapidly reduce fungal burden then replaced by another drug)
For treatment of systemic fungal disease, how is ampB administered?
slow IV infusion
How is intrathecal injections of ampB tolerated in patients?
poorly
What 2 categories can ampB toxicity be classified as?
- immediate rxns (related to infusion) 2. slower occurring ones
What are the ampB infusion related toxicities?
fever, chills, muscle spasms, vomiting, headache, hypotension
In which patients does ampB infusion related toxicity occur?
all of them
How are infusion related toxicities of ampB controlled?
slow your roll and slow down that infusion rate OR premedicate them with antipyretics, antihistamines, meperidine, or corticosteroids OR administer a test dose and see how bad they react
What is the most significant toxicity of ampB?
renal damage
In which patients do renal toxicities occur with ampB?
nearly all
What is the reversible component of renal toxicity with ampB?
decreased renal perfusion
What is the irreversible component of renal toxicity with ampB?
renal tubular injury and resulting dysfunction
When does this irreversible renal injury happen?
with prolonged ampB administration
How does renal toxicity with ampB commonly present?
renal tubular acidosis and severe K and Mg wasting
Why is it common to administer normal saline infusions with daily doses of ampB?
decreases renal injury
What type of molecule is Flucytosine?
pyrimidine analog
Is FC water soluble?
yes
Is FC’s spectrum of action broader or narrower than ampB?
much narrower
What types of formulations is FC available in?
oral only
Is FC well or poorly absorbed?
well
How long after oral FC administration do serum concentrations peak?
1-2 hours
What’s the serum protein binding of FC like?
low
How is FC’s penetration into body compartments?
very good
Can FC penetrate CSF?
yes
How is FC eliminated from the body?
glomerular filtration
What is the half-life of FC?
3-4 hours
Is FC removed by dialysis?
yes
What is responsible for FC toxicity?
FC levels rise rapidly with renal impairment
In what patient populations is FC toxicity most likely to occur in?
AIDS and renal insufficient patients
In patients with renal impairment, what should be checked periodically to avoid toxicity?
peak serum concentrations (keep within 50-100 mcg/mL
What fungal enzyme takes up FC?
cytosine permease
List the order of compounds FC is converted into once it enters the fungal cell?
first to 5-FU then to 5-FdUMP + 5-FUTP
What does 5-FdUMP do?
inhibits DNA synthesis
What does 5-FUTP do?
inhibits RNA synthesis
How is FC selective?
human cells are unable to convert the parent drug to its active metabolites
What 2 drugs does FC show synergism with?
AmpB and Azoles
How is administration of ampB with FC beneficial?
ampB pores increase uptake of FC in fungal cells
How is resistance to FC conferred in fungal cells?
altered metabolism of FC
Does FC resistance develop rapidly with FC monotherapy?
yes: it is never used by itself
What do the adverse effects of FC result from?
when FC is metabolized to the toxic antineoplastic compound Fluorouracil (thought to be done by intestinal flora)
What are the most common adverse effects of FC?
bone marrow toxicity with anemia, leukopenia, and thrombocytopenia (messes up liver enzymes less frequently)
Can a toxic form of enterocolitis form with FC use?
yes
Does FC have a broad or narrow therapeutic window?
narrow: high levels=increased risk of toxicity, subtherapeutic levels=rapidly developing resistance
How can a physician reduce the incidence of toxic rxns with FC?
measure drug concentration frequently (especially when administered with ampB)
What is the difference between imidazoles and triazoles?
triazoles have the extra N in the five-membered azole ring
Which drugs are the imidazoles?
ketoconazole, miconazole, clotrimazole
Which drugs are the triazoles?
itraconazole, fluconazole, voriconazole, posaconazole
Which 2 imidazoles are only used in topical therapy?
miconazole and clotrimazole
What is the mechanism of action of azoles?
reduce ergosterol synthesis by inhibiting fungal CYP450s
How are azoles selective?
they have a greater affinity for fungal CYP450s than human CYP450s
Why do imidazoles have a higher incidence of drug interactions and adverse effects?
they are less selective than triazoles
Do azoles have a narrow or broad spectrum of action?
broad
Are azoles as a group relatively toxic or non-toxic?
non-toxic
What is the most common adverse rxn with azoles?
relatively minor GI upset
What have all azoles been reported to cause?
abnormalities in liver enzymes (rarely reported to cause clinical hepatitis)
Why are all azoles prone to drug drug interactions?
because they affect human CYP450s to some extent
Which triazole is more likely to inhibit human CYP450s?
ketoconazole
What are 2 adverse effects seen in males with ketoconazole use? Why?
gynecomastia (grow boobies) and impotence: results b/c ketoconazole inhibits a CYP of steroid synthesis and thus inhibits testosterone production
What 2 formulations is itraconazole available in?
oral and IV
Itraconazole absorption is increased by what 2 things?
food and low gastric pH
Reduced bioavailability of itraconazole is observed when taken with what drugs?
rifamycins (rifampin, rifabutin, rifapentine)
Does itraconazole affect human steroid synthesis?
no
What limits the effectiveness of itraconazole?
reduced bioavailability
What carrier molecule is used with itraconazole to enhance solubility and bioavailability?
cyclodextran
Do ketoconazole and itraconazole penetrate CSF well?
no
What is the water solubility of fluconazole?
high
What is the CSF penetration of fluconazole?
yes
Are drug drug interactions with fluconazole frequently observed?
no: fluconazole has least effect on human CYPs of all the azoles
What is the Black Box Warning of itraconazole for?
congestive heart failure
What are the 2 reasons why fluconazole has the widest therapeutic index of all the azoles?
- least effect on human CYPs 2. best GI tolerance
Is aggressive dosing allowed with fluconazole?
yes: same 2 reasons it has the widest therapeutic index
What formulations is fluconazole available in?
oral and IV
What formulations is voriconazole available in?
oral and IV
Is voriconazole absorbed well orally?
yes
Does voriconazole have a high bioavailability with oral administration?
yes: exceeds 90%
Which azole binds more to proteins: voriconazole or itraconazole?
itraconazole
What is the metabolism of voriconazole?
hepatic
Dose reduction of voriconazole is required when combined with which drugs? Why?
cyclosporine, tacrolimus, HMG-CoA reductase inhibitors: b/c voriconazole inhibits human CYP3A4
Which human CYP does voriconazole inhibit?
CYP3A4
Are rash and elevated hepatic enzymes observed with voriconazole use?
yes
What visual disturbances does voriconazole cause?
blurring and changes in color vision or brightness
When do visual disturbances occur with voriconazole use? How long does it take for them to go away?
immediately after dose is given: go away within 30 minutes
What is commonly observed in patients receiving chronic voriconazole oral therapy?
photosensitivity dermatitis
What formulation is posaconazole only availbe in?
liquid oral
How would you increase absorption of posaconazole?
with meals high in fat
Posaconazole rapidly distributes to all tissues, resulting in what?
high tissue levels but low blood levels
Which human CYP does posaconazole inhibit?
CYP3A4
Which drugs does posaconazole have drug drug interactions with?
tacrolimus and cyclosporine (CYP3A4 substrates)
What spectrum of action does posaconazole have?
the broadest of all the azoles
Which drugs comprise the Echinocandins family?
caspofungin, micafungin, anidulafungin
What is the molecular structure of echinocandins?
large cyclic peptides linked to a long chain fatty acid
What is the only formulation the echinocandins are available in?
IV
How is capsofungin administered?
single loading dose of 70mg followed by daily dose of 50mg
Is capsofungin water soluble?
yes
What is the protein binding of capsofungin like?
high
What is the half-life of capsofungin?
9-11 hours
How are the metabolites of capsofungin excreted?
kidneys and GI tract
When are dosage adjustments of capsofungin required?
severe hepatic insufficiency
Does micafungin have similar properties of capsofungin?
yes
What is the half-life of micafungin?
11-15 hours
What is the half-life of anidulafungin?
24-48 hours
What is echinocandins’ mechanism of action?
inhibits synthesis of beta-(1-3)-glucan thus disrupting the fungal cell wall and causing cell death
What is the tolerance of echinocandins?
extremely well tolerated
What are the minor side effects of echinocandins?
minor GI and flushing side effects
Which drug should be avoided in combination with capsofungin? What happens?
cyclosporine: elevated liver enzymes
Which drugs does micafungin increase levels of?
nifedipine, cyclosporine, sirolimus
What may occur with IV infusion of anidulafungin?
histamine release
Does anidulafungin have any significant drug drug interactions?
no
What are the 2 oral systemic antifungal drugs used for treatment of mucocutaneous infections?
griseofulvin and terbinafine
Is griseofulvin fungicidal or fungistatic?
fungistatic
Is griseofulvin water soluble?
no: very insoluble
What species is griseofulvin derived from?
a penicillium species
What form is griseofulvin administered in?
microcrystalline form
How would you increase absorption of griseofulvin?
give with fatty foods
When griseofulvin is deposited in newly forming skin, what does it bind to? What does this binding do?
keratin: prevents skin from new infection
How long must griseofulvin be administered for skin and hair infections?
2-6 weeks
Griseofulvin administration for nail infections may be required for how long?
months (to allow regrowth of the new protected nail)
What are the adverse effects of griseofulvin?
allergic syndrome that resembles serum sickness and hepatitis
Which drugs elicit a drug drug interaction when given with griseofulvin?
warfarin and phenobarbital
What type of molecule is terbinafine?
synthetic allylamine
What type of formulation is terbinafine available in?
oral
Is terbinafine fungicidal or fungistatic?
fungicidal
Does terbinafine bind to keratin like griseofulvin?
yes
How is terbinafine like the azoles?
it inhibits ergosterol biosynthesis
What is terbinafine’s mechanism of action?
inhibits the fungal enzyme squalene epoxidase which leads to a toxic accumulation of the sterol squalene
What are the rare adverse effects of terbinafine?
GI upset and headache
Does terbinafine have any drug drug interactions?
no
What type of molecule is nystatin?
polyene macrolide (like ampB)
What formulation is nystatin available in?
topical only (too toxic for parenteral administration): available as creams, ointments, suppositories, and other forms for application to the skin and mucous membranes
How well is nystatin absorbed from skin, mucous membranes, and the GI tract?
not absorbed to a significant degree
Is nystatin very toxic?
no b/c it isn’t absorbed well
What limits oral use of nystatin?
unpleasant taste
What are the 2 azoles that are used topically?
clotrimazole and miconazole
Are topical clotrimazole and miconazole available over-the-counter?
yes
Are oral clotrimazol troches better tasting than nystatin?
yes
What about absorption and adverse effects of topical clotrimazole and miconazole?
absorption is negligible and adverse effects are rare
What other forms of ketoconazole are there?
topical and shampoo forms
What are the 2 allylamines available as topical creams? Are they prescription or over-the-counter?
terbinafine and naftifine: prescription
