B3.046 Anti-fungal and Anti-parasitic Therapy Flashcards
why is it difficult to achieve selective toxicity when targeting fungi?
they are eukaryotic
who is at most risk of fungal infections?
debilitated or immunosuppressed patients
superinfections
what are some of the main targets for anti-fungal chemo?
fungal cell membrane
fungal cell wall
DNA, RNA synthesis
Amphotericin B mechanism
polyene antibiotic (big, complex, double bonds) binds to ergosterol in fungal membranes
what is ergosterol
small lipid molecule
required component of fungal cell membrace
binding it disrupts the membrane structure
Amphotericin B pharmacokinetics
IV or intrathecal
widely distributed except CNS
very slow excretion, half life of 2 weeks
discuss liposomal amphotericin B reservoirs
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
Amphotericin B clinical uses
severe systemic mycoses
wide range of fungal infection
initial intervention–other drugs used for maintenance/cure
Amphotericin B adverse effects
usually see chills, fever, nausea, vomiting, headache (premeditate w antipyretics, antihistamines, analgesics)nephrotoxicity common, often irreversible
numerous other common adverse effects
**amphoterrible
5-Fluorocytosine mechanism
activated by fungal cytosine deaminase
converted to 5-fluorouracil
blocks DNA and RNA synthesis by inducing thymineless death
5-Fluorocytosine pharmacokinetics
oral
widely distributed, including CNS
excreted in urine
urine levels 10x serum levels
5-Fluorocytosine adverse effects
low toxicity to patient
not activated in mammalian cells
5-Fluorocytosine clinical use
narrow spectrum- Cryptococcus, some candida
resistance develops rapidly, only use with amphotericin B or itraconazole
what are the anti-fungal azoles?
ketoconazole
itraconazole
fluconazole
voriconazole
mechanism of all anti-fungal azoles
inhibit ergosterol synthesis (fungal CYPs)
Ketoconazole pharmacokinetics
oral (seldom used)
topical available
absorbed and distributed, except for CNS
Ketoconazole clinical uses
wide range of fungi
seldom used systemically due to adverse effects
Ketoconazole adverse effects
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
Itraconazole pharmacokinetics
oral (low bioavailability)
IV
less effect on mammalian CYPs than ketoconazole
Itraconazole clinical uses
histoplasma
blasomyces
sporothrix
Fluconazole pharmacokinetics
most widely used oral and IV water soluble high bioavailability, goof CSF delivery more selective for fungal CYPs
Fluconazole clinical uses
cryptococcal meningitis
candidemia
mucocutaneous candidiasis
Voriconazole pharmacokinetics
newest triazole
IV or oral (90% bioavailability)
metabolized in liver, but little mammalian CYP inhibition
Voriconazole adverse effects
visual disturbances in 30% of patients
Voriconazole clinical uses
candida and dimorphic fungi
better tolerated and more effective than Amphotericin B against invasive Aspergillus
Caspofungin mechanism
inhibits synthesis of B(1-3)glucan for cell wall
incomplete cell wall causes lysis
Caspofungin pharmacokinetics
large cyclic peptide linked to fatty acid
IV
highly protein bound, slow metabolism
excreted in urine and feces
Caspofungin adverse effects
minor GI effects
flushing
Caspofungin clinical uses
Candida, empiric anti-fungal therapy (in febrile neutropenia)
salvage therapy for amphotericin resistant aspergillus
what are the 3 anti-fungal agents used for mucocutaneous infections
nystatin - topical
griseofulvin - systemic for topical infection
terbinafine- systemic for topical infection
Nystatin pharmacokinetics
topical
similar to amphotericin B, too toxic for systemic use
Griseofulvin pharmacokinetics
administer orally, concentrates in keratinized tissue
Griseofulvin clinical uses
ringworm athlete’s foot
Terbinafine mechanism/pharmacokinetics
similar pharmacokinetics to griseofulvin, but can also be used topically
inhibits squalene epoxidase (ergosterol synthesis)
what are the species of protozoan that cause malaria?
plasmodium falciparum
plasmodium malariae
plasmodium vivax
plasmodium ovale
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
how does primaquine differ from other antimalarials
ONLY ONE that affects tissue schizonts
all other affect blood schizonts
Chloroquine mechanism
alters metabolism/detoxification of heme by parasite
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)
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
why must prophylaxis be taken after return from travel?
make sure all parasites have gone through maturation and left liver
Chloroquine adverse effects
generally well tolerated pruitis GI mild headache may exacerbate psoriasis or porphyria
Chloroquine resistance
widespread in South America, Africa, Asia
common in falciparum, increasing in vivax
P-glycoprotein pumping mechanism
Mefloquine mechanism
unknown
may be similar to Chloroquine
Mefloquine pharmacokinetics
only oral
well absorbed and distributed
metabolized in liver, excreted in feces
Mefloquine adverse effects
GI
CNS
possible psychotropic effects
Mefloquine clinical uses
prophylaxis or treatment of Chloroquine resistant malaria
Quinine mechanism
may alter heme metabolism, actual mechanism unclear
from Cinchona bark
Quinine pharmacokinetics
oral well absorbed Cmax and AUC higher in malaria patients doesn't cross blood brain barrier metabolized by CYP3A4, other CYPs
Quinine clinical uses
used for chloroquine resistant p.falciparum
Quinine adverse effects
cinchonism (headache, sweating, nausea, tinnitus, dizziness, blurred vision)
QT prolongation, slows heart conduction and alters cardiac rhythms
Quinine clinical uses
acute treatment when chloroquine resistance is present and adverse effects are tolerable
Atovaquone mechanism
inhibits electron transport chain, mitochondrial function
Atovaquone pharmacokinetics
oral
poor absorption
high protein binding 2-3 day half life
Proguanil mechanism
inhibits protozoal dihydrofolate reductase
Proguanil pharmacokinetics
well absorbed
half life 12 hours
extensive metabolism by CYP2C19
active metabolite (cycloguanil)
Atovaquone/Proguanil (Malarone) clinical uses
used for prophylaxis or treatment of resistant p.falciparum
Atovaquone/Proguanil (Malarone) adverse effects
GI
headache
dizziness
anorexia
Fansidar (pyrimethamine-sulfadoxine) mechanism
anti-folate combo
blocks synthesis/utilization of folic acid
some GI distress
cutaneous reactions (sometimes severe)
Fansidar pharmacokinetics
well absorbed and distributed
excreted in urine
Fansidar clinical use
effective blood schizonticide for p.falciparum
for chloroquine resistant p.falciparum
slow acting, cannot be used for acute attack
what is Artemisinin?
traditional Chinese medicine
activated by oxidative metabolism–free radicals, alkylation
rapidly acting blood schizonticide
what is Artesunate?
same mechanism as Artemisinin, but IV
longer half life
used for severe P.falciparum
emerging first line therapy
how does Primaquine differ from other anti-malarials?
tissue schizonticide
does not work for blood borne disease
Primaquine mechanism
metabolites are intracellular antioxidants
Primaquine clinical use
used in combo w chloroquine for prophylaxis or cure of vivax and ovale
Primaquine adverse effects
GI distress
hemolytic anemia in G6PDH deficiency
Metronidazole mechanism
tissue amebicide
nitroimidazole–activated by electron donation
particularly effective for anaerobic/hypoxic sites
Metronidazole pharmacokinetics
oral or IV
well absorbed and distributed, including CNS and bone
cleared in urine following hepatic metabolism
Metronidazole clinical uses
intestinal, extraintestinal, and urogenital protozoal infections
(including Trichomoniasis, Giardiasis, Amebiasis)
Metronidazole adverse effects
many and common: nausea, headache, dry mouth, leukopenia disulfiram effect (aversion treatment for alcoholics, induced hangover)
Nitozoxanide mechanism
inhibits electron transport system pyruvate-ferredoxin oxidoreductase (PFOR)
Nitozoxanide pharmacokinetics
oral
well absorbed but quantitatively metabolized (de-acetylated)
tizoxanide is active metabolite
most secreted into bile
Nitozoxanide clinical uses
treatment of Giardia lambia and Cryptosporidia parvum
metronidazole-resistant strains
Nitroxanide adverse effects
few
better tolerated than metronidazole
Pentamidine mechanism
unknown
Pentamidine pharmacokinetics
IV, IM or aerosol
concentrated in liver, spleen, kidneys
slowly released from those sites
doesn’t enter CNS
Pentamidine clinical uses
aerosols used for treatment/prophylaxis against Pneumocystis pneumonia
Pentamidine adverse effects
can cause respiratory stimulation followed by depression; hypotension, anemia
adverse effects less common with aerosol administration
what is targeted in anti-helminthic chemotherapy?
target is multi-cellular organism
mobility/contractile system in parasites are important targets
Mebendazole mechanism
blocks microtubule synthesis, blocks vesicle and organelle movement
Mebendazole pharmacokinetics
oral
less than 10% absorbed
rapidly metabolized, excreted in urine
Mebendazole clinical uses
wide spectrum anti-helminthic
effective against pinworm, hookworm, Ascaris
Mebendazole adverse effects
dose limited by GI effects
possibly embryotoxic
Albendazole mechanism
interferes with microtubule aggregation, alters glucose uptake
Albendazole pharmacokinetics
rapidly and completely metabolized in liver
conjugates excreted in urine
Albendazole clinical uses
wide spectrum anti-helminthic
Ivermectin mechanism
inhibits chloride channels, causes paralysis and death
very minor effects on human GABA receptors, does not cross blood-brain barrier (MDR1 substrate)
Ivermectin pharmacokinetics
oral
well absorbed and distributed
half life 16-18 hours
metabolized by CYP3A4 and other CYPs
Ivermectin adverse effects
headache
dizziness
drowsiness
Ivermectin clinical uses
all intestinal Strongyloidiasis and Onchocercasias
subcutaneous nodules, corneal and anterior chamber
