Pharmacology Of GI Anti-Parasites Flashcards
Enteric protozoa survival and continuous destruction depends on:
Efficient protein synthesis
Ethanol/Acetate fermentation, source of ATP
Muscular worms Have a rudimentary neuromuscular system which consist of:
Glutamate-gated chloride channels
Inhibitory GABA transmitter
Microtubule for locomotion and cell division
Metronidazole
Interacts with ferredoxins and/or other protozoal specific nitroreductase enzymes and electron transport proteins that participate in metabolic electron removal reactions.
The nitro group of metronidazole is able to serve as an electron acceptor, forming reduced cytotoxic compounds that bind to proteins and DNA, resulting in death of the E. histolytica trophozoites.
Metronidazole selectivity
Highly effective against Entamoeba histolytica trophozoites in tissue but ineffective against intraluminal ameba.
Symptomatic ameba infection is typically treated first with metronidazole, then a second agent (paromomycin or iodquinol).
Clinical Applications of Metronidazole
Amebic diarrhea
Dysentery of colic.
Liver abscess: 10 times more common in men than women
Diarrhea caused by Balantidiasis
Clinical Spectrum of Metronidazole
Most anaerobic bacteria and parasites (protozoa)
Helminthes
Mechanism of Resistance - Metronidazole
Null mutations in the oxygen-insensitive NADPH nitroreductase conveys resistance to metronidazole
Decrease expression of ferredoxins in some protozoal species cause low-level resistance to metronidazole
Decrease PFOR activity, decrease permeability into Giardia
Increase expression of superoxide dismutase (ameba)
PFOR
PFOR converts pyravute –> acetyl coA
Why do luminal parasites exhibit minimal resistance against metronidazole?
Luminal parasites are usually diploid so that a single mutation will not necessary convey resistance
Luminal parasites have few metabolic alternatives to PFOR activity
Metronidazole is hydrophilic so that over-expression of P-glycoprotein which convey resistant to hydrophobic drugs does not increases metronidazole efflux.
Adverse Effects of Metronidazole
GI discomfort, headaches, occasional neuropathy and metallic taste.
Disulfiram-like reaction: metronidazole can cause severe nausea and flushing if taken with alcohol (see diagram)
AVOID in pregnant women, nursing mothers and children under 3yrs of age.
Why use tinidazole over metronidazole?
2nd generation nitroimidazole, greater efficacy and fewer side effects, more tolerable than metronidazole.
Drug course is shorter than metronidazole.
Like metronidazole, it is ineffective against intraluminal amebic trophozoites.
Clinical Applications of Tinidazole?
Giardiasis
Amebiasis
Vaginal trichomoniasis
Adverse Effects of Tinidazole
GI discomfort, occasional metallic taste (similar to metronidazole but are milder and rarer)
Not recommended during 1st trimester pregnancy, breastfeeding or in children < 3yrs old.
Nitazoxanide MOA
Inhibits PFOR in protozoa and anaerobic bacteria
Effective against helminths (mechanism unknown)
Nitazoxanide is structurally similar to what?
thiamine pyrophosphate and metronidazole
Clinical Applications of Nitazoxanide
Giardiasis (in children)
Cryptosporidiosis (in both children and adults)
Ascaris lumbricoides
What drug is used to treat a child with giardia?
Nitazoxanide
ADE NItazoxanide
Well tolerated, few adverse effects (but abdominal pain, diarrhea, vomiting and headaches have been reported albeit far-in-between)
Category B in pregnancy
What drug class is paromomycin in? Why is it used to treat luminal enteric protozoa?
An aminoglycoside, poor absorption from the GI tract increases efficacy against enteric protozoa.
Paromomycin MOA
Bind to the 16S rRNA of the 30S subunit. Induces ribosomes to misread mRNA during elongation –> synthesis of proteins containing incorrect amino acids.
Paramomycin Clinical Indications
For management of amebiasis, cryptosporidial diarrhea, but ineffective against extra-intestinal amebiasis.
Paromomycin ADES
Abdominal cramps, nausea, vomiting, ototoxicity, steatorrhea.
Limited data on pregnancy safety, but has poor oral absorption, use with caution for giardiasis in pregnancy.
Why is Iodoquinol used to treat luminal protozoa?
Enteric amebicide, poor GI absorption, excreted in feces.
Iodoquinol MOA
May be an iron chelator, deprives parasites of essential metabolic mineral.
Iodoquinol monotherapy is ineffective against ________.
Iodoquinol monotherapy is ineffective against ________.
Iodoquinol ADES
Abdominal cramps
Anal itching
Thyroid enlargement
Iodoquinol is contraindicated in what settings?
Hypersensitivity to iodine
Liver failure
How is Balantidiasis treated?
Treated with tetracyclines.
Alternatively with metronidazole or iodoquinol: nitazoxanide have been tried with significant success
How is Cryptosporidiosis treated?
Tend to persist in AIDs patients
Diarrhea, dehydration and electrolyte depletion
Most effective treatment is HAART, nitazoxanide is currently the only FDA approved therapy. Paramomycin has been used.
How is Giardiasis treated?
Common amongst children in day-care and nurseries
5-day course of metronidazole usually effective, single dose of tinidazole likely superior to metronidazole
During pregnancy: paromomycin appear safer
Children less than 12yrs old: nitazoxanide and tinidazole, the only two FDA-approved
Mebendazole MOA
Inhibits tubulin polymerization by binding to beta-tubulin. Inhibition of tubulin polymerization disrupts nematodal motility and DNA replication –> immobility and death of the worms.
Also destroys the protoscolex (the future head of the adult cestode).
Clinical Applications
Necator americanus (hookworm)
Diphyllobothrium latum (tapeworm – which could be visualized and killed with diatrizoate)
Trichuris trichiura (roundworm or whipworm - mebendazole)
Ascaris lumbricoides
Mebendazole ADES
Thiabendazole causes significant nausea, vomiting and anorexia even at therapeutic doses.
Mebendazole and albendazole are better tolerated and are frequently used
Albendazole has the highest oral bioavailability of all three drugs.
MEBENDAZOLE IS TERATOGENIC, MUST AVOID IN PREGNANCY.
Praziquantel MOA
Increases the parasite membrane permeability to calcium, resulting in contraction and paralysis of the worms.
Praziquantal Clinical Indications
Drug of choice for trematodes (fluke worm), Taeniasis and Diphyllobothrium latum (tape worm), neurocysticercosis, including many other parasites.
Praziquantel ADES
Use in neurocysticercosis, can cause pruritus, skin rash, worsening eosinophilia. Alleviated with concomitant corticosteroids.
Severe reactions may include: meningismus, mental changes, seizures, arachnoiditis, hyperthermia and intracranial hypertension
Praziquantel Contraindications
contraindicated in ocular cysticercosis, permanent damage to the eyes may occur
Increases abortion rates in lab animals, avoided in pregnancy when possible
High potential for dizziness, drowsiness, patient should not drive while on praziquantel.
What drugs can lower plasma levels of Praziquantel?
Corticosteroids.
Ivermectin MOA
Potentiates and/or directly activates glutamate-gated chloride channels (mediates inhibitory neurotransmission in nematodes) in nematode plasma membranes –> hyperpolarization of neuromuscular cells and causes pharyngeal paralysis.
Also potentiates the release of GABA from presynaptic terminals –> direct activation of GABA receptors –> increase in GABA-mediated transmission of signal in peripheral nerves –> hyperpolarization.
ULTIMATE RESULT IS BLOCKADE OF NEUROMUSCULAR TRANSMISSION AND PARALYSIS F THE WORM.
Ivermectin Clinical Applications
Strongyloides stercoralis (thread worm)
Ascaris lumbricoides (round worms)
Ivermectin ADES
Mazzotti-type reactions: Headaches, dizziness, weakness, rash, pruritus, edema, abdominal pain, hypotension and fever.
Mazzotti reactions are due to inflammatory or allergic response to dying microfilariae.
Ivermectin Contraindications
Concomitant use of ivermectin with barbiturates, benzodiazepine, valproic acid should be avoided.
Avoid use during pregnancy, safety in children <5 yrs has not been established.
Treatment of Ascaris Lumbricoides
Mebendazole, albendazole (preferred for asymptomatic to moderate infections.
use with caution in severe ascaris infection, risk of appendicitis, blockade of common bile duct, intestinal obstruction and perforation with peritonitis)
Pyrantel pamoate is preferred for severe ascaris infections.
Diphyllobothrium latum (fish tape worm) (associated with megaloblastic anemia due to B12 deficiency)
Praziquantel
Enterobius vermicularis (pinworm):
Pyrantel pamoate, mebendazole and albendazole are highly effective
Must treat close family members.
Necator americanus (hookworm) (blood feeding worms in the intestines).
Albendazole (first choice, superior to mebendazole at removing adult hookworms), mebendazole or ivermectin can also be used.
Strongyloides stercoralis (threadworm): can complete life cycle in humans.
Ivermectin is drug of choice, mebendazole and albendazole can be used.
Trichuris trichiura (whipworm):
Mebendazole, albendazole most effective therapy.
