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Pharmacology > Antifungals > Flashcards

Antifungals Flashcards

1
Q

What type of molecule is Amphotericin B?

A

ampoteric polyene macrolide

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2
Q

Is Amphotericin B soluble in water?

A

no: it is nearly insoluble in water

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3
Q

What is Amphotericin B compounded with for IV injection?

A

sodium desoxycholate

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4
Q

Is AmpB absorbed well or poorly from the GI tract?

A

poorly

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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

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6
Q

What percent of ampB is bound by serum proteins?

A

90%

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7
Q

How is ampB eliminated?

A

Mostly metabolized but some excreted slowly in the urine.

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8
Q

What is the serum half life of ampB?

A

15 days

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9
Q

Is dose adjustment required for a patient with hepatic impairment, renal impairment, or dialysis?

A

no

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10
Q

Where is ampB distributed in the body?

A

widely distributed to most tissues

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11
Q

Does ampB penetrate CSF well?

A

No: only 2-3%

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12
Q

Is ampB therapy limited by toxicity?

A

Yes

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13
Q

What’s the most concerning toxicity caused by ampB?

A

drug-induced renal impairment

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14
Q

Why is ampB packaged in a lipid formulation?

A

lower toxicity

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15
Q

How does the lipid formulation allow lower toxicity?

A

binds to mammalian membranes less readily

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16
Q

Do the lipid delivery vehicles serve as an ampB reservoir?

A

Yes, which reduces nonspecific binding to human cell membranes

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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

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18
Q

What is ampB’s mechanism of action?

A

Binds to ergosterol and forms a pore in fungi cell membranes

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19
Q

How is ampB selective?

A

only binds to ergosterol and not cholesterol in human cell membranes

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20
Q

Which side of ampB binds lipids/ergosterols?

A

double bond rich side

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21
Q

Which side of ampB binds water?

A

hydroxyl rich side

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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)

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23
Q

How does the formation of the pore lead to fungi cell death?

A

allows leakage of intracellular ions and macromolecules

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24
Q

What accounts for the toxicity of ampB?

A

some binding of human cholesterol does occur

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25
Q

When does ampB resistance occur?

A

when ergosterol binding is impaired

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26
Q

How do fungi confer resistance to ampB? 2 ways.

A
  1. decrease membrane concentration of ergosterol 2. modify binding site on ergosterol to decrease affinity
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27
Q

Does ampB have the broadest spectrum of action among all the antifungals?

A

yes

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28
Q

What limits ampB’s use clinically?

A

it’s toxicity: mainly used in life-threatening mycotic infxns (usually used initially to rapidly reduce fungal burden then replaced by another drug)

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29
Q

For treatment of systemic fungal disease, how is ampB administered?

A

slow IV infusion

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30
Q

How is intrathecal injections of ampB tolerated in patients?

A

poorly

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31
Q

What 2 categories can ampB toxicity be classified as?

A
  1. immediate rxns (related to infusion) 2. slower occurring ones
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32
Q

What are the ampB infusion related toxicities?

A

fever, chills, muscle spasms, vomiting, headache, hypotension

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33
Q

In which patients does ampB infusion related toxicity occur?

A

all of them

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34
Q

How are infusion related toxicities of ampB controlled?

A

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

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35
Q

What is the most significant toxicity of ampB?

A

renal damage

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36
Q

In which patients do renal toxicities occur with ampB?

A

nearly all

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37
Q

What is the reversible component of renal toxicity with ampB?

A

decreased renal perfusion

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38
Q

What is the irreversible component of renal toxicity with ampB?

A

renal tubular injury and resulting dysfunction

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39
Q

When does this irreversible renal injury happen?

A

with prolonged ampB administration

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40
Q

How does renal toxicity with ampB commonly present?

A

renal tubular acidosis and severe K and Mg wasting

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41
Q

Why is it common to administer normal saline infusions with daily doses of ampB?

A

decreases renal injury

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42
Q

What type of molecule is Flucytosine?

A

pyrimidine analog

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43
Q

Is FC water soluble?

A

yes

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44
Q

Is FC’s spectrum of action broader or narrower than ampB?

A

much narrower

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45
Q

What types of formulations is FC available in?

A

oral only

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46
Q

Is FC well or poorly absorbed?

A

well

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47
Q

How long after oral FC administration do serum concentrations peak?

A

1-2 hours

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48
Q

What’s the serum protein binding of FC like?

A

low

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49
Q

How is FC’s penetration into body compartments?

A

very good

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50
Q

Can FC penetrate CSF?

A

yes

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51
Q

How is FC eliminated from the body?

A

glomerular filtration

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52
Q

What is the half-life of FC?

A

3-4 hours

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53
Q

Is FC removed by dialysis?

A

yes

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54
Q

What is responsible for FC toxicity?

A

FC levels rise rapidly with renal impairment

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55
Q

In what patient populations is FC toxicity most likely to occur in?

A

AIDS and renal insufficient patients

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56
Q

In patients with renal impairment, what should be checked periodically to avoid toxicity?

A

peak serum concentrations (keep within 50-100 mcg/mL

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57
Q

What fungal enzyme takes up FC?

A

cytosine permease

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58
Q

List the order of compounds FC is converted into once it enters the fungal cell?

A

first to 5-FU then to 5-FdUMP + 5-FUTP

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59
Q

What does 5-FdUMP do?

A

inhibits DNA synthesis

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60
Q

What does 5-FUTP do?

A

inhibits RNA synthesis

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61
Q

How is FC selective?

A

human cells are unable to convert the parent drug to its active metabolites

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62
Q

What 2 drugs does FC show synergism with?

A

AmpB and Azoles

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63
Q

How is administration of ampB with FC beneficial?

A

ampB pores increase uptake of FC in fungal cells

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64
Q

How is resistance to FC conferred in fungal cells?

A

altered metabolism of FC

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65
Q

Does FC resistance develop rapidly with FC monotherapy?

A

yes: it is never used by itself

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66
Q

What do the adverse effects of FC result from?

A

when FC is metabolized to the toxic antineoplastic compound Fluorouracil (thought to be done by intestinal flora)

67
Q

What are the most common adverse effects of FC?

A

bone marrow toxicity with anemia, leukopenia, and thrombocytopenia (messes up liver enzymes less frequently)

68
Q

Can a toxic form of enterocolitis form with FC use?

A

yes

69
Q

Does FC have a broad or narrow therapeutic window?

A

narrow: high levels=increased risk of toxicity, subtherapeutic levels=rapidly developing resistance

70
Q

How can a physician reduce the incidence of toxic rxns with FC?

A

measure drug concentration frequently (especially when administered with ampB)

71
Q

What is the difference between imidazoles and triazoles?

A

triazoles have the extra N in the five-membered azole ring

72
Q

Which drugs are the imidazoles?

A

ketoconazole, miconazole, clotrimazole

73
Q

Which drugs are the triazoles?

A

itraconazole, fluconazole, voriconazole, posaconazole

74
Q

Which 2 imidazoles are only used in topical therapy?

A

miconazole and clotrimazole

75
Q

What is the mechanism of action of azoles?

A

reduce ergosterol synthesis by inhibiting fungal CYP450s

76
Q

How are azoles selective?

A

they have a greater affinity for fungal CYP450s than human CYP450s

77
Q

Why do imidazoles have a higher incidence of drug interactions and adverse effects?

A

they are less selective than triazoles

78
Q

Do azoles have a narrow or broad spectrum of action?

A

broad

79
Q

Are azoles as a group relatively toxic or non-toxic?

A

non-toxic

80
Q

What is the most common adverse rxn with azoles?

A

relatively minor GI upset

81
Q

What have all azoles been reported to cause?

A

abnormalities in liver enzymes (rarely reported to cause clinical hepatitis)

82
Q

Why are all azoles prone to drug drug interactions?

A

because they affect human CYP450s to some extent

83
Q

Which triazole is more likely to inhibit human CYP450s?

A

ketoconazole

84
Q

What are 2 adverse effects seen in males with ketoconazole use? Why?

A

gynecomastia (grow boobies) and impotence: results b/c ketoconazole inhibits a CYP of steroid synthesis and thus inhibits testosterone production

85
Q

What 2 formulations is itraconazole available in?

A

oral and IV

86
Q

Itraconazole absorption is increased by what 2 things?

A

food and low gastric pH

87
Q

Reduced bioavailability of itraconazole is observed when taken with what drugs?

A

rifamycins (rifampin, rifabutin, rifapentine)

88
Q

Does itraconazole affect human steroid synthesis?

A

no

89
Q

What limits the effectiveness of itraconazole?

A

reduced bioavailability

90
Q

What carrier molecule is used with itraconazole to enhance solubility and bioavailability?

A

cyclodextran

91
Q

Do ketoconazole and itraconazole penetrate CSF well?

A

no

92
Q

What is the water solubility of fluconazole?

A

high

93
Q

What is the CSF penetration of fluconazole?

A

yes

94
Q

Are drug drug interactions with fluconazole frequently observed?

A

no: fluconazole has least effect on human CYPs of all the azoles

95
Q

What is the Black Box Warning of itraconazole for?

A

congestive heart failure

96
Q

What are the 2 reasons why fluconazole has the widest therapeutic index of all the azoles?

A
  1. least effect on human CYPs 2. best GI tolerance
97
Q

Is aggressive dosing allowed with fluconazole?

A

yes: same 2 reasons it has the widest therapeutic index

98
Q

What formulations is fluconazole available in?

A

oral and IV

99
Q

What formulations is voriconazole available in?

A

oral and IV

100
Q

Is voriconazole absorbed well orally?

A

yes

101
Q

Does voriconazole have a high bioavailability with oral administration?

A

yes: exceeds 90%

102
Q

Which azole binds more to proteins: voriconazole or itraconazole?

A

itraconazole

103
Q

What is the metabolism of voriconazole?

A

hepatic

104
Q

Dose reduction of voriconazole is required when combined with which drugs? Why?

A

cyclosporine, tacrolimus, HMG-CoA reductase inhibitors: b/c voriconazole inhibits human CYP3A4

105
Q

Which human CYP does voriconazole inhibit?

A

CYP3A4

106
Q

Are rash and elevated hepatic enzymes observed with voriconazole use?

A

yes

107
Q

What visual disturbances does voriconazole cause?

A

blurring and changes in color vision or brightness

108
Q

When do visual disturbances occur with voriconazole use? How long does it take for them to go away?

A

immediately after dose is given: go away within 30 minutes

109
Q

What is commonly observed in patients receiving chronic voriconazole oral therapy?

A

photosensitivity dermatitis

110
Q

What formulation is posaconazole only availbe in?

A

liquid oral

111
Q

How would you increase absorption of posaconazole?

A

with meals high in fat

112
Q

Posaconazole rapidly distributes to all tissues, resulting in what?

A

high tissue levels but low blood levels

113
Q

Which human CYP does posaconazole inhibit?

A

CYP3A4

114
Q

Which drugs does posaconazole have drug drug interactions with?

A

tacrolimus and cyclosporine (CYP3A4 substrates)

115
Q

What spectrum of action does posaconazole have?

A

the broadest of all the azoles

116
Q

Which drugs comprise the Echinocandins family?

A

caspofungin, micafungin, anidulafungin

117
Q

What is the molecular structure of echinocandins?

A

large cyclic peptides linked to a long chain fatty acid

118
Q

What is the only formulation the echinocandins are available in?

A

IV

119
Q

How is capsofungin administered?

A

single loading dose of 70mg followed by daily dose of 50mg

120
Q

Is capsofungin water soluble?

A

yes

121
Q

What is the protein binding of capsofungin like?

A

high

122
Q

What is the half-life of capsofungin?

A

9-11 hours

123
Q

How are the metabolites of capsofungin excreted?

A

kidneys and GI tract

124
Q

When are dosage adjustments of capsofungin required?

A

severe hepatic insufficiency

125
Q

Does micafungin have similar properties of capsofungin?

A

yes

126
Q

What is the half-life of micafungin?

A

11-15 hours

127
Q

What is the half-life of anidulafungin?

A

24-48 hours

128
Q

What is echinocandins’ mechanism of action?

A

inhibits synthesis of beta-(1-3)-glucan thus disrupting the fungal cell wall and causing cell death

129
Q

What is the tolerance of echinocandins?

A

extremely well tolerated

130
Q

What are the minor side effects of echinocandins?

A

minor GI and flushing side effects

131
Q

Which drug should be avoided in combination with capsofungin? What happens?

A

cyclosporine: elevated liver enzymes

132
Q

Which drugs does micafungin increase levels of?

A

nifedipine, cyclosporine, sirolimus

133
Q

What may occur with IV infusion of anidulafungin?

A

histamine release

134
Q

Does anidulafungin have any significant drug drug interactions?

A

no

135
Q

What are the 2 oral systemic antifungal drugs used for treatment of mucocutaneous infections?

A

griseofulvin and terbinafine

136
Q

Is griseofulvin fungicidal or fungistatic?

A

fungistatic

137
Q

Is griseofulvin water soluble?

A

no: very insoluble

138
Q

What species is griseofulvin derived from?

A

a penicillium species

139
Q

What form is griseofulvin administered in?

A

microcrystalline form

140
Q

How would you increase absorption of griseofulvin?

A

give with fatty foods

141
Q

When griseofulvin is deposited in newly forming skin, what does it bind to? What does this binding do?

A

keratin: prevents skin from new infection

142
Q

How long must griseofulvin be administered for skin and hair infections?

A

2-6 weeks

143
Q

Griseofulvin administration for nail infections may be required for how long?

A

months (to allow regrowth of the new protected nail)

144
Q

What are the adverse effects of griseofulvin?

A

allergic syndrome that resembles serum sickness and hepatitis

145
Q

Which drugs elicit a drug drug interaction when given with griseofulvin?

A

warfarin and phenobarbital

146
Q

What type of molecule is terbinafine?

A

synthetic allylamine

147
Q

What type of formulation is terbinafine available in?

A

oral

148
Q

Is terbinafine fungicidal or fungistatic?

A

fungicidal

149
Q

Does terbinafine bind to keratin like griseofulvin?

A

yes

150
Q

How is terbinafine like the azoles?

A

it inhibits ergosterol biosynthesis

151
Q

What is terbinafine’s mechanism of action?

A

inhibits the fungal enzyme squalene epoxidase which leads to a toxic accumulation of the sterol squalene

152
Q

What are the rare adverse effects of terbinafine?

A

GI upset and headache

153
Q

Does terbinafine have any drug drug interactions?

A

no

154
Q

What type of molecule is nystatin?

A

polyene macrolide (like ampB)

155
Q

What formulation is nystatin available in?

A

topical only (too toxic for parenteral administration): available as creams, ointments, suppositories, and other forms for application to the skin and mucous membranes

156
Q

How well is nystatin absorbed from skin, mucous membranes, and the GI tract?

A

not absorbed to a significant degree

157
Q

Is nystatin very toxic?

A

no b/c it isn’t absorbed well

158
Q

What limits oral use of nystatin?

A

unpleasant taste

159
Q

What are the 2 azoles that are used topically?

A

clotrimazole and miconazole

160
Q

Are topical clotrimazole and miconazole available over-the-counter?

A

yes

161
Q

Are oral clotrimazol troches better tasting than nystatin?

A

yes

162
Q

What about absorption and adverse effects of topical clotrimazole and miconazole?

A

absorption is negligible and adverse effects are rare

163
Q

What other forms of ketoconazole are there?

A

topical and shampoo forms

164
Q

What are the 2 allylamines available as topical creams? Are they prescription or over-the-counter?

A

terbinafine and naftifine: prescription

Pharmacology (5 decks)

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