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IBI Test 3 > B3.046 Anti-fungal and Anti-parasitic Therapy > Flashcards

B3.046 Anti-fungal and Anti-parasitic Therapy Flashcards

1
Q

why is it difficult to achieve selective toxicity when targeting fungi?

A

they are eukaryotic

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2
Q

who is at most risk of fungal infections?

A

debilitated or immunosuppressed patients

superinfections

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3
Q

what are some of the main targets for anti-fungal chemo?

A

fungal cell membrane
fungal cell wall
DNA, RNA synthesis

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4
Q

Amphotericin B mechanism

A 
polyene antibiotic (big, complex, double bonds)
binds to ergosterol in fungal membranes
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5
Q

what is ergosterol

A

small lipid molecule
required component of fungal cell membrace
binding it disrupts the membrane structure

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6
Q

Amphotericin B pharmacokinetics

A

IV or intrathecal
widely distributed except CNS
very slow excretion, half life of 2 weeks

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7
Q

discuss liposomal amphotericin B reservoirs

A

the liposome has lower affinity for drug than does fungal membrane, but a higher affinity for the drug than the patient membrane
drug selectively distributes from liposome to fungal membrane, not to human membrane

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8
Q

Amphotericin B clinical uses

A

severe systemic mycoses
wide range of fungal infection
initial intervention–other drugs used for maintenance/cure

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9
Q

Amphotericin B adverse effects

A

usually see chills, fever, nausea, vomiting, headache (premeditate w antipyretics, antihistamines, analgesics)nephrotoxicity common, often irreversible
numerous other common adverse effects
**amphoterrible

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10
Q

5-Fluorocytosine mechanism

A

activated by fungal cytosine deaminase
converted to 5-fluorouracil
blocks DNA and RNA synthesis by inducing thymineless death

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11
Q

5-Fluorocytosine pharmacokinetics

A

oral
widely distributed, including CNS
excreted in urine
urine levels 10x serum levels

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12
Q

5-Fluorocytosine adverse effects

A

low toxicity to patient

not activated in mammalian cells

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13
Q

5-Fluorocytosine clinical use

A

narrow spectrum- Cryptococcus, some candida

resistance develops rapidly, only use with amphotericin B or itraconazole

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14
Q

what are the anti-fungal azoles?

A

ketoconazole
itraconazole
fluconazole
voriconazole

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15
Q

mechanism of all anti-fungal azoles

A

inhibit ergosterol synthesis (fungal CYPs)

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16
Q

Ketoconazole pharmacokinetics

A

oral (seldom used)
topical available
absorbed and distributed, except for CNS

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17
Q

Ketoconazole clinical uses

A

wide range of fungi

seldom used systemically due to adverse effects

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18
Q

Ketoconazole adverse effects

A

nausea, vomiting, anorexia (20%)
hepatotoxicity (1-2%)
blocks adrenal steroidogenesis- gyncecomastia
-used as adjunct therapy for prostate cancer
inhibits drug metabolism (CYP3A4 and other CYPS)
interactions with cyclosporine, many other drugs

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19
Q

Itraconazole pharmacokinetics

A

oral (low bioavailability)
IV
less effect on mammalian CYPs than ketoconazole

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20
Q

Itraconazole clinical uses

A

histoplasma
blasomyces
sporothrix

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21
Q

Fluconazole pharmacokinetics

A 
most widely used
oral and IV
water soluble
high bioavailability, goof CSF delivery
more selective for fungal CYPs
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22
Q

Fluconazole clinical uses

A

cryptococcal meningitis
candidemia
mucocutaneous candidiasis

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23
Q

Voriconazole pharmacokinetics

A

newest triazole
IV or oral (90% bioavailability)
metabolized in liver, but little mammalian CYP inhibition

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24
Q

Voriconazole adverse effects

A

visual disturbances in 30% of patients

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25
Q

Voriconazole clinical uses

A

candida and dimorphic fungi

better tolerated and more effective than Amphotericin B against invasive Aspergillus

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26
Q

Caspofungin mechanism

A

inhibits synthesis of B(1-3)glucan for cell wall

incomplete cell wall causes lysis

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27
Q

Caspofungin pharmacokinetics

A

large cyclic peptide linked to fatty acid
IV
highly protein bound, slow metabolism
excreted in urine and feces

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28
Q

Caspofungin adverse effects

A

minor GI effects

flushing

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29
Q

Caspofungin clinical uses

A

Candida, empiric anti-fungal therapy (in febrile neutropenia)
salvage therapy for amphotericin resistant aspergillus

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30
Q

what are the 3 anti-fungal agents used for mucocutaneous infections

A

nystatin - topical
griseofulvin - systemic for topical infection
terbinafine- systemic for topical infection

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31
Q

Nystatin pharmacokinetics

A

topical

similar to amphotericin B, too toxic for systemic use

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32
Q

Griseofulvin pharmacokinetics

A

administer orally, concentrates in keratinized tissue

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33
Q

Griseofulvin clinical uses

A

ringworm athlete’s foot

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34
Q

Terbinafine mechanism/pharmacokinetics

A

similar pharmacokinetics to griseofulvin, but can also be used topically
inhibits squalene epoxidase (ergosterol synthesis)

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35
Q

what are the species of protozoan that cause malaria?

A

plasmodium falciparum
plasmodium malariae
plasmodium vivax
plasmodium ovale

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36
Q

what is the distinction between falciparum/malariae vs vivax/ovale

A

first two have single cycle

second two have multiple cycles, leave a colony in the liver

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37
Q

how does primaquine differ from other antimalarials

A

ONLY ONE that affects tissue schizonts

all other affect blood schizonts

38
Q

Chloroquine mechanism

A

alters metabolism/detoxification of heme by parasite

39
Q

Chloroquine pharmacokinetics

A 
oral or parenternal
rapid, complete absorption
wide distribution
excreted in urine, 25% as metabolite
loading dose necessary for acute treatment (accumulates over time)
40
Q

Chloroquine clinical uses

A 
highly effective blood schizonticide
clears parasitemia in all four Plasmodia
curative for first 2
used with primaquine for second 2
prophylactic- begin 1 week before travel, continue 4 weeks after
41
Q

why must prophylaxis be taken after return from travel?

A

make sure all parasites have gone through maturation and left liver

42
Q

Chloroquine adverse effects

A 
generally well tolerated
pruitis
GI
mild headache
may exacerbate psoriasis or porphyria
43
Q

Chloroquine resistance

A

widespread in South America, Africa, Asia
common in falciparum, increasing in vivax
P-glycoprotein pumping mechanism

44
Q

Mefloquine mechanism

A

unknown

may be similar to Chloroquine

45
Q

Mefloquine pharmacokinetics

A

only oral
well absorbed and distributed
metabolized in liver, excreted in feces

46
Q

Mefloquine adverse effects

A

GI
CNS
possible psychotropic effects

47
Q

Mefloquine clinical uses

A

prophylaxis or treatment of Chloroquine resistant malaria

48
Q

Quinine mechanism

A

may alter heme metabolism, actual mechanism unclear

from Cinchona bark

49
Q

Quinine pharmacokinetics

A 
oral
well absorbed
Cmax and AUC higher in malaria patients
doesn't cross blood brain barrier
metabolized by CYP3A4, other CYPs
50
Q

Quinine clinical uses

A

used for chloroquine resistant p.falciparum

51
Q

Quinine adverse effects

A

cinchonism (headache, sweating, nausea, tinnitus, dizziness, blurred vision)
QT prolongation, slows heart conduction and alters cardiac rhythms

52
Q

Quinine clinical uses

A

acute treatment when chloroquine resistance is present and adverse effects are tolerable

53
Q

Atovaquone mechanism

A

inhibits electron transport chain, mitochondrial function

54
Q

Atovaquone pharmacokinetics

A

oral
poor absorption
high protein binding 2-3 day half life

55
Q

Proguanil mechanism

A

inhibits protozoal dihydrofolate reductase

56
Q

Proguanil pharmacokinetics

A

well absorbed
half life 12 hours
extensive metabolism by CYP2C19
active metabolite (cycloguanil)

57
Q

Atovaquone/Proguanil (Malarone) clinical uses

A

used for prophylaxis or treatment of resistant p.falciparum

58
Q

Atovaquone/Proguanil (Malarone) adverse effects

A

GI
headache
dizziness
anorexia

59
Q

Fansidar (pyrimethamine-sulfadoxine) mechanism

A

anti-folate combo
blocks synthesis/utilization of folic acid
some GI distress
cutaneous reactions (sometimes severe)

60
Q

Fansidar pharmacokinetics

A

well absorbed and distributed

excreted in urine

61
Q

Fansidar clinical use

A

effective blood schizonticide for p.falciparum
for chloroquine resistant p.falciparum
slow acting, cannot be used for acute attack

62
Q

what is Artemisinin?

A

traditional Chinese medicine
activated by oxidative metabolism–free radicals, alkylation
rapidly acting blood schizonticide

63
Q

what is Artesunate?

A

same mechanism as Artemisinin, but IV
longer half life
used for severe P.falciparum
emerging first line therapy

64
Q

how does Primaquine differ from other anti-malarials?

A

tissue schizonticide

does not work for blood borne disease

65
Q

Primaquine mechanism

A

metabolites are intracellular antioxidants

66
Q

Primaquine clinical use

A

used in combo w chloroquine for prophylaxis or cure of vivax and ovale

67
Q

Primaquine adverse effects

A

GI distress

hemolytic anemia in G6PDH deficiency

68
Q

Metronidazole mechanism

A

tissue amebicide
nitroimidazole–activated by electron donation
particularly effective for anaerobic/hypoxic sites

69
Q

Metronidazole pharmacokinetics

A

oral or IV
well absorbed and distributed, including CNS and bone
cleared in urine following hepatic metabolism

70
Q

Metronidazole clinical uses

A

intestinal, extraintestinal, and urogenital protozoal infections
(including Trichomoniasis, Giardiasis, Amebiasis)

71
Q

Metronidazole adverse effects

A 
many and common: nausea, headache, dry mouth, leukopenia
disulfiram effect (aversion treatment for alcoholics, induced hangover)
72
Q

Nitozoxanide mechanism

A

inhibits electron transport system pyruvate-ferredoxin oxidoreductase (PFOR)

73
Q

Nitozoxanide pharmacokinetics

A

oral
well absorbed but quantitatively metabolized (de-acetylated)
tizoxanide is active metabolite
most secreted into bile

74
Q

Nitozoxanide clinical uses

A

treatment of Giardia lambia and Cryptosporidia parvum

metronidazole-resistant strains

75
Q

Nitroxanide adverse effects

A

few

better tolerated than metronidazole

76
Q

Pentamidine mechanism

A

unknown

77
Q

Pentamidine pharmacokinetics

A

IV, IM or aerosol
concentrated in liver, spleen, kidneys
slowly released from those sites
doesn’t enter CNS

78
Q

Pentamidine clinical uses

A

aerosols used for treatment/prophylaxis against Pneumocystis pneumonia

79
Q

Pentamidine adverse effects

A

can cause respiratory stimulation followed by depression; hypotension, anemia
adverse effects less common with aerosol administration

80
Q

what is targeted in anti-helminthic chemotherapy?

A

target is multi-cellular organism

mobility/contractile system in parasites are important targets

81
Q

Mebendazole mechanism

A

blocks microtubule synthesis, blocks vesicle and organelle movement

82
Q

Mebendazole pharmacokinetics

A

oral
less than 10% absorbed
rapidly metabolized, excreted in urine

83
Q

Mebendazole clinical uses

A

wide spectrum anti-helminthic

effective against pinworm, hookworm, Ascaris

84
Q

Mebendazole adverse effects

A

dose limited by GI effects

possibly embryotoxic

85
Q

Albendazole mechanism

A

interferes with microtubule aggregation, alters glucose uptake

86
Q

Albendazole pharmacokinetics

A

rapidly and completely metabolized in liver

conjugates excreted in urine

87
Q

Albendazole clinical uses

A

wide spectrum anti-helminthic

88
Q

Ivermectin mechanism

A

inhibits chloride channels, causes paralysis and death

very minor effects on human GABA receptors, does not cross blood-brain barrier (MDR1 substrate)

89
Q

Ivermectin pharmacokinetics

A

oral
well absorbed and distributed
half life 16-18 hours
metabolized by CYP3A4 and other CYPs

90
Q

Ivermectin adverse effects

A

headache
dizziness
drowsiness

91
Q

Ivermectin clinical uses

A

all intestinal Strongyloidiasis and Onchocercasias

subcutaneous nodules, corneal and anterior chamber

IBI Test 3 (19 decks)

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