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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
Voriconazole clinical uses
candida and dimorphic fungi | better tolerated and more effective than Amphotericin B against invasive Aspergillus
26
Caspofungin mechanism
inhibits synthesis of B(1-3)glucan for cell wall | incomplete cell wall causes lysis
27
Caspofungin pharmacokinetics
large cyclic peptide linked to fatty acid IV highly protein bound, slow metabolism excreted in urine and feces
28
Caspofungin adverse effects
minor GI effects | flushing
29
Caspofungin clinical uses
Candida, empiric anti-fungal therapy (in febrile neutropenia) salvage therapy for amphotericin resistant aspergillus
30
what are the 3 anti-fungal agents used for mucocutaneous infections
nystatin - topical griseofulvin - systemic for topical infection terbinafine- systemic for topical infection
31
Nystatin pharmacokinetics
topical | similar to amphotericin B, too toxic for systemic use
32
Griseofulvin pharmacokinetics
administer orally, concentrates in keratinized tissue
33
Griseofulvin clinical uses
ringworm athlete's foot
34
Terbinafine mechanism/pharmacokinetics
similar pharmacokinetics to griseofulvin, but can also be used topically inhibits squalene epoxidase (ergosterol synthesis)
35
what are the species of protozoan that cause malaria?
plasmodium falciparum plasmodium malariae plasmodium vivax plasmodium ovale
36
what is the distinction between falciparum/malariae vs vivax/ovale
first two have single cycle | second two have multiple cycles, leave a colony in the liver
37
how does primaquine differ from other antimalarials
ONLY ONE that affects tissue schizonts | all other affect blood schizonts
38
Chloroquine mechanism
alters metabolism/detoxification of heme by parasite
39
Chloroquine pharmacokinetics
``` oral or parenternal rapid, complete absorption wide distribution excreted in urine, 25% as metabolite loading dose necessary for acute treatment (accumulates over time) ```
40
Chloroquine clinical uses
``` 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
why must prophylaxis be taken after return from travel?
make sure all parasites have gone through maturation and left liver
42
Chloroquine adverse effects
``` generally well tolerated pruitis GI mild headache may exacerbate psoriasis or porphyria ```
43
Chloroquine resistance
widespread in South America, Africa, Asia common in falciparum, increasing in vivax P-glycoprotein pumping mechanism
44
Mefloquine mechanism
unknown | may be similar to Chloroquine
45
Mefloquine pharmacokinetics
only oral well absorbed and distributed metabolized in liver, excreted in feces
46
Mefloquine adverse effects
GI CNS possible psychotropic effects
47
Mefloquine clinical uses
prophylaxis or treatment of Chloroquine resistant malaria
48
Quinine mechanism
may alter heme metabolism, actual mechanism unclear | from Cinchona bark
49
Quinine pharmacokinetics
``` oral well absorbed Cmax and AUC higher in malaria patients doesn't cross blood brain barrier metabolized by CYP3A4, other CYPs ```
50
Quinine clinical uses
used for chloroquine resistant p.falciparum
51
Quinine adverse effects
cinchonism (headache, sweating, nausea, tinnitus, dizziness, blurred vision) QT prolongation, slows heart conduction and alters cardiac rhythms
52
Quinine clinical uses
acute treatment when chloroquine resistance is present and adverse effects are tolerable
53
Atovaquone mechanism
inhibits electron transport chain, mitochondrial function
54
Atovaquone pharmacokinetics
oral poor absorption high protein binding 2-3 day half life
55
Proguanil mechanism
inhibits protozoal dihydrofolate reductase
56
Proguanil pharmacokinetics
well absorbed half life 12 hours extensive metabolism by CYP2C19 active metabolite (cycloguanil)
57
Atovaquone/Proguanil (Malarone) clinical uses
used for prophylaxis or treatment of resistant p.falciparum
58
Atovaquone/Proguanil (Malarone) adverse effects
GI headache dizziness anorexia
59
Fansidar (pyrimethamine-sulfadoxine) mechanism
anti-folate combo blocks synthesis/utilization of folic acid some GI distress cutaneous reactions (sometimes severe)
60
Fansidar pharmacokinetics
well absorbed and distributed | excreted in urine
61
Fansidar clinical use
effective blood schizonticide for p.falciparum for chloroquine resistant p.falciparum slow acting, cannot be used for acute attack
62
what is Artemisinin?
traditional Chinese medicine activated by oxidative metabolism--free radicals, alkylation rapidly acting blood schizonticide
63
what is Artesunate?
same mechanism as Artemisinin, but IV longer half life used for severe P.falciparum emerging first line therapy
64
how does Primaquine differ from other anti-malarials?
tissue schizonticide | does not work for blood borne disease
65
Primaquine mechanism
metabolites are intracellular antioxidants
66
Primaquine clinical use
used in combo w chloroquine for prophylaxis or cure of vivax and ovale
67
Primaquine adverse effects
GI distress | hemolytic anemia in G6PDH deficiency
68
Metronidazole mechanism
tissue amebicide nitroimidazole--activated by electron donation particularly effective for anaerobic/hypoxic sites
69
Metronidazole pharmacokinetics
oral or IV well absorbed and distributed, including CNS and bone cleared in urine following hepatic metabolism
70
Metronidazole clinical uses
intestinal, extraintestinal, and urogenital protozoal infections (including Trichomoniasis, Giardiasis, Amebiasis)
71
Metronidazole adverse effects
``` many and common: nausea, headache, dry mouth, leukopenia disulfiram effect (aversion treatment for alcoholics, induced hangover) ```
72
Nitozoxanide mechanism
inhibits electron transport system pyruvate-ferredoxin oxidoreductase (PFOR)
73
Nitozoxanide pharmacokinetics
oral well absorbed but quantitatively metabolized (de-acetylated) tizoxanide is active metabolite most secreted into bile
74
Nitozoxanide clinical uses
treatment of Giardia lambia and Cryptosporidia parvum | metronidazole-resistant strains
75
Nitroxanide adverse effects
few | better tolerated than metronidazole
76
Pentamidine mechanism
unknown
77
Pentamidine pharmacokinetics
IV, IM or aerosol concentrated in liver, spleen, kidneys slowly released from those sites doesn't enter CNS
78
Pentamidine clinical uses
aerosols used for treatment/prophylaxis against Pneumocystis pneumonia
79
Pentamidine adverse effects
can cause respiratory stimulation followed by depression; hypotension, anemia adverse effects less common with aerosol administration
80
what is targeted in anti-helminthic chemotherapy?
target is multi-cellular organism | mobility/contractile system in parasites are important targets
81
Mebendazole mechanism
blocks microtubule synthesis, blocks vesicle and organelle movement
82
Mebendazole pharmacokinetics
oral less than 10% absorbed rapidly metabolized, excreted in urine
83
Mebendazole clinical uses
wide spectrum anti-helminthic | effective against pinworm, hookworm, Ascaris
84
Mebendazole adverse effects
dose limited by GI effects | possibly embryotoxic
85
Albendazole mechanism
interferes with microtubule aggregation, alters glucose uptake
86
Albendazole pharmacokinetics
rapidly and completely metabolized in liver | conjugates excreted in urine
87
Albendazole clinical uses
wide spectrum anti-helminthic
88
Ivermectin mechanism
inhibits chloride channels, causes paralysis and death | very minor effects on human GABA receptors, does not cross blood-brain barrier (MDR1 substrate)
89
Ivermectin pharmacokinetics
oral well absorbed and distributed half life 16-18 hours metabolized by CYP3A4 and other CYPs
90
Ivermectin adverse effects
headache dizziness drowsiness
91
Ivermectin clinical uses
all intestinal Strongyloidiasis and Onchocercasias | subcutaneous nodules, corneal and anterior chamber

IBI Test 3 (19 decks)

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