Antifungals Flashcards
(164 cards)
1
Q
What type of molecule is Amphotericin B?
A
ampoteric polyene macrolide
2
Q
Is Amphotericin B soluble in water?
A
no: it is nearly insoluble in water
3
Q
What is Amphotericin B compounded with for IV injection?
A
sodium desoxycholate
4
Q
Is AmpB absorbed well or poorly from the GI tract?
A
poorly
5
Q
Can oral ampB be used for treatment of systemic disease?
A
No: oral only effective on fungi within the lumen of the GI tract
6
Q
What percent of ampB is bound by serum proteins?
A
90%
7
Q
How is ampB eliminated?
A
Mostly metabolized but some excreted slowly in the urine.
8
Q
What is the serum half life of ampB?
A
15 days
9
Q
Is dose adjustment required for a patient with hepatic impairment, renal impairment, or dialysis?
A
no
10
Q
Where is ampB distributed in the body?
A
widely distributed to most tissues
11
Q
Does ampB penetrate CSF well?
A
No: only 2-3%
12
Q
Is ampB therapy limited by toxicity?
A
Yes
13
Q
What’s the most concerning toxicity caused by ampB?
A
drug-induced renal impairment
14
Q
Why is ampB packaged in a lipid formulation?
A
lower toxicity
15
Q
How does the lipid formulation allow lower toxicity?
A
binds to mammalian membranes less readily
16
Q
Do the lipid delivery vehicles serve as an ampB reservoir?
A
Yes, which reduces nonspecific binding to human cell membranes
17
Q
List all of the advantages of liposomal ampB delivery?
A
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
18
Q
What is ampB’s mechanism of action?
A
Binds to ergosterol and forms a pore in fungi cell membranes
19
Q
How is ampB selective?
A
only binds to ergosterol and not cholesterol in human cell membranes
20
Q
Which side of ampB binds lipids/ergosterols?
A
double bond rich side
21
Q
Which side of ampB binds water?
A
hydroxyl rich side
22
Q
Why is the amphipathic characteristic of ampB important?
A
facilitates pore formation (hydrophobic side on outside of pore and hydrophilic side lines canal of pore)
23
Q
How does the formation of the pore lead to fungi cell death?
A
allows leakage of intracellular ions and macromolecules
24
Q
What accounts for the toxicity of ampB?
A
some binding of human cholesterol does occur
25
When does ampB resistance occur?
when ergosterol binding is impaired
26
How do fungi confer resistance to ampB? 2 ways.
1. decrease membrane concentration of ergosterol 2. modify binding site on ergosterol to decrease affinity
27
Does ampB have the broadest spectrum of action among all the antifungals?
yes
28
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)
29
For treatment of systemic fungal disease, how is ampB administered?
slow IV infusion
30
How is intrathecal injections of ampB tolerated in patients?
poorly
31
What 2 categories can ampB toxicity be classified as?
1. immediate rxns (related to infusion) 2. slower occurring ones
32
What are the ampB infusion related toxicities?
fever, chills, muscle spasms, vomiting, headache, hypotension
33
In which patients does ampB infusion related toxicity occur?
all of them
34
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
35
What is the most significant toxicity of ampB?
renal damage
36
In which patients do renal toxicities occur with ampB?
nearly all
37
What is the reversible component of renal toxicity with ampB?
decreased renal perfusion
38
What is the irreversible component of renal toxicity with ampB?
renal tubular injury and resulting dysfunction
39
When does this irreversible renal injury happen?
with prolonged ampB administration
40
How does renal toxicity with ampB commonly present?
renal tubular acidosis and severe K and Mg wasting
41
Why is it common to administer normal saline infusions with daily doses of ampB?
decreases renal injury
42
What type of molecule is Flucytosine?
pyrimidine analog
43
Is FC water soluble?
yes
44
Is FC's spectrum of action broader or narrower than ampB?
much narrower
45
What types of formulations is FC available in?
oral only
46
Is FC well or poorly absorbed?
well
47
How long after oral FC administration do serum concentrations peak?
1-2 hours
48
What's the serum protein binding of FC like?
low
49
How is FC's penetration into body compartments?
very good
50
Can FC penetrate CSF?
yes
51
How is FC eliminated from the body?
glomerular filtration
52
What is the half-life of FC?
3-4 hours
53
Is FC removed by dialysis?
yes
54
What is responsible for FC toxicity?
FC levels rise rapidly with renal impairment
55
In what patient populations is FC toxicity most likely to occur in?
AIDS and renal insufficient patients
56
In patients with renal impairment, what should be checked periodically to avoid toxicity?
peak serum concentrations (keep within 50-100 mcg/mL
57
What fungal enzyme takes up FC?
cytosine permease
58
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
59
What does 5-FdUMP do?
inhibits DNA synthesis
60
What does 5-FUTP do?
inhibits RNA synthesis
61
How is FC selective?
human cells are unable to convert the parent drug to its active metabolites
62
What 2 drugs does FC show synergism with?
AmpB and Azoles
63
How is administration of ampB with FC beneficial?
ampB pores increase uptake of FC in fungal cells
64
How is resistance to FC conferred in fungal cells?
altered metabolism of FC
65
Does FC resistance develop rapidly with FC monotherapy?
yes: it is never used by itself
66
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)
67
What are the most common adverse effects of FC?
bone marrow toxicity with anemia, leukopenia, and thrombocytopenia (messes up liver enzymes less frequently)
68
Can a toxic form of enterocolitis form with FC use?
yes
69
Does FC have a broad or narrow therapeutic window?
narrow: high levels=increased risk of toxicity, subtherapeutic levels=rapidly developing resistance
70
How can a physician reduce the incidence of toxic rxns with FC?
measure drug concentration frequently (especially when administered with ampB)
71
What is the difference between imidazoles and triazoles?
triazoles have the extra N in the five-membered azole ring
72
Which drugs are the imidazoles?
ketoconazole, miconazole, clotrimazole
73
Which drugs are the triazoles?
itraconazole, fluconazole, voriconazole, posaconazole
74
Which 2 imidazoles are only used in topical therapy?
miconazole and clotrimazole
75
What is the mechanism of action of azoles?
reduce ergosterol synthesis by inhibiting fungal CYP450s
76
How are azoles selective?
they have a greater affinity for fungal CYP450s than human CYP450s
77
Why do imidazoles have a higher incidence of drug interactions and adverse effects?
they are less selective than triazoles
78
Do azoles have a narrow or broad spectrum of action?
broad
79
Are azoles as a group relatively toxic or non-toxic?
non-toxic
80
What is the most common adverse rxn with azoles?
relatively minor GI upset
81
What have all azoles been reported to cause?
abnormalities in liver enzymes (rarely reported to cause clinical hepatitis)
82
Why are all azoles prone to drug drug interactions?
because they affect human CYP450s to some extent
83
Which triazole is more likely to inhibit human CYP450s?
ketoconazole
84
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
85
What 2 formulations is itraconazole available in?
oral and IV
86
Itraconazole absorption is increased by what 2 things?
food and low gastric pH
87
Reduced bioavailability of itraconazole is observed when taken with what drugs?
rifamycins (rifampin, rifabutin, rifapentine)
88
Does itraconazole affect human steroid synthesis?
no
89
What limits the effectiveness of itraconazole?
reduced bioavailability
90
What carrier molecule is used with itraconazole to enhance solubility and bioavailability?
cyclodextran
91
Do ketoconazole and itraconazole penetrate CSF well?
no
92
What is the water solubility of fluconazole?
high
93
What is the CSF penetration of fluconazole?
yes
94
Are drug drug interactions with fluconazole frequently observed?
no: fluconazole has least effect on human CYPs of all the azoles
95
What is the Black Box Warning of itraconazole for?
congestive heart failure
96
What are the 2 reasons why fluconazole has the widest therapeutic index of all the azoles?
1. least effect on human CYPs 2. best GI tolerance
97
Is aggressive dosing allowed with fluconazole?
yes: same 2 reasons it has the widest therapeutic index
98
What formulations is fluconazole available in?
oral and IV
99
What formulations is voriconazole available in?
oral and IV
100
Is voriconazole absorbed well orally?
yes
101
Does voriconazole have a high bioavailability with oral administration?
yes: exceeds 90%
102
Which azole binds more to proteins: voriconazole or itraconazole?
itraconazole
103
What is the metabolism of voriconazole?
hepatic
104
Dose reduction of voriconazole is required when combined with which drugs? Why?
cyclosporine, tacrolimus, HMG-CoA reductase inhibitors: b/c voriconazole inhibits human CYP3A4
105
Which human CYP does voriconazole inhibit?
CYP3A4
106
Are rash and elevated hepatic enzymes observed with voriconazole use?
yes
107
What visual disturbances does voriconazole cause?
blurring and changes in color vision or brightness
108
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
109
What is commonly observed in patients receiving chronic voriconazole oral therapy?
photosensitivity dermatitis
110
What formulation is posaconazole only availbe in?
liquid oral
111
How would you increase absorption of posaconazole?
with meals high in fat
112
Posaconazole rapidly distributes to all tissues, resulting in what?
high tissue levels but low blood levels
113
Which human CYP does posaconazole inhibit?
CYP3A4
114
Which drugs does posaconazole have drug drug interactions with?
tacrolimus and cyclosporine (CYP3A4 substrates)
115
What spectrum of action does posaconazole have?
the broadest of all the azoles
116
Which drugs comprise the Echinocandins family?
caspofungin, micafungin, anidulafungin
117
What is the molecular structure of echinocandins?
large cyclic peptides linked to a long chain fatty acid
118
What is the only formulation the echinocandins are available in?
IV
119
How is capsofungin administered?
single loading dose of 70mg followed by daily dose of 50mg
120
Is capsofungin water soluble?
yes
121
What is the protein binding of capsofungin like?
high
122
What is the half-life of capsofungin?
9-11 hours
123
How are the metabolites of capsofungin excreted?
kidneys and GI tract
124
When are dosage adjustments of capsofungin required?
severe hepatic insufficiency
125
Does micafungin have similar properties of capsofungin?
yes
126
What is the half-life of micafungin?
11-15 hours
127
What is the half-life of anidulafungin?
24-48 hours
128
What is echinocandins' mechanism of action?
inhibits synthesis of beta-(1-3)-glucan thus disrupting the fungal cell wall and causing cell death
129
What is the tolerance of echinocandins?
extremely well tolerated
130
What are the minor side effects of echinocandins?
minor GI and flushing side effects
131
Which drug should be avoided in combination with capsofungin? What happens?
cyclosporine: elevated liver enzymes
132
Which drugs does micafungin increase levels of?
nifedipine, cyclosporine, sirolimus
133
What may occur with IV infusion of anidulafungin?
histamine release
134
Does anidulafungin have any significant drug drug interactions?
no
135
What are the 2 oral systemic antifungal drugs used for treatment of mucocutaneous infections?
griseofulvin and terbinafine
136
Is griseofulvin fungicidal or fungistatic?
fungistatic
137
Is griseofulvin water soluble?
no: very insoluble
138
What species is griseofulvin derived from?
a penicillium species
139
What form is griseofulvin administered in?
microcrystalline form
140
How would you increase absorption of griseofulvin?
give with fatty foods
141
When griseofulvin is deposited in newly forming skin, what does it bind to? What does this binding do?
keratin: prevents skin from new infection
142
How long must griseofulvin be administered for skin and hair infections?
2-6 weeks
143
Griseofulvin administration for nail infections may be required for how long?
months (to allow regrowth of the new protected nail)
144
What are the adverse effects of griseofulvin?
allergic syndrome that resembles serum sickness and hepatitis
145
Which drugs elicit a drug drug interaction when given with griseofulvin?
warfarin and phenobarbital
146
What type of molecule is terbinafine?
synthetic allylamine
147
What type of formulation is terbinafine available in?
oral
148
Is terbinafine fungicidal or fungistatic?
fungicidal
149
Does terbinafine bind to keratin like griseofulvin?
yes
150
How is terbinafine like the azoles?
it inhibits ergosterol biosynthesis
151
What is terbinafine's mechanism of action?
inhibits the fungal enzyme squalene epoxidase which leads to a toxic accumulation of the sterol squalene
152
What are the rare adverse effects of terbinafine?
GI upset and headache
153
Does terbinafine have any drug drug interactions?
no
154
What type of molecule is nystatin?
polyene macrolide (like ampB)
155
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
156
How well is nystatin absorbed from skin, mucous membranes, and the GI tract?
not absorbed to a significant degree
157
Is nystatin very toxic?
no b/c it isn't absorbed well
158
What limits oral use of nystatin?
unpleasant taste
159
What are the 2 azoles that are used topically?
clotrimazole and miconazole
160
Are topical clotrimazole and miconazole available over-the-counter?
yes
161
Are oral clotrimazol troches better tasting than nystatin?
yes
162
What about absorption and adverse effects of topical clotrimazole and miconazole?
absorption is negligible and adverse effects are rare
163
What other forms of ketoconazole are there?
topical and shampoo forms
164
What are the 2 allylamines available as topical creams? Are they prescription or over-the-counter?
terbinafine and naftifine: prescription
