Gi System- Antiparasitics Anthelmintics By Maloney

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GI System- Antiparasitics Anthelmintics by Maloney

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GI System- Antiparasitics Anthelmintics by Maloney

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What are the target organisms for these antiparasitic drugs?

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Entamoeba histolytica
Giardia
Cryptosporidium
Trichomonas vaginalis

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Nitroimidazoles Agents

what type of organisms are these good for?

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metronidazole
tinidazole

good for anaerobic organisms (parasites and bacteria--> h. pylori)

metronidazole (for example), within the anaerobic organism, is activated by redox stuff and then disrupts the DNA, killing it.

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Metronidazole/Tinidazole MoA, pharmacokinetics

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-The inactive form (prodrug) is taken up by anaerobic organisms
-Reduced ferredoxin (generated from the decarboxylation of pyruvate by pyruvate-ferredoxin oxidoreductase) can transfer its electrons to metronidazole
-Anaerobic organisms also express nitroreductase that selectively reduces metronidazole and in the process oxidizes NADPH to NADP
-The active form disrupts DNA's helical structure and inhibits nucleic acid synthesis causing cell or organism death
-It is equally effective against dividing and non dividing cells

Oral (Absorbed completely)
Widespread distribution including the CNS

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What are the three type of people with amebiasis (trophozoites)?

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1. asympotmatic (cyst passer)
2. intestinal ulcer--> bloody diarrhea
3. liver abscess--> into the rest of the body, even the brain

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Note About Amebiasis Treatment...clinical use of Metronidazole/Tinidazole

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Each type of infection has a different therapy
Drugs used for treatment are called ‘amebicides’ and are usually divided into

LUMINICIDAL agents …. Effective against organisms in the lumen of the GI tract
TISSUECIDAL agents … Effective against the organism in the tissues

Symptomatic intestinal amebiasis or with extraintestinal infections (DOC)
-Mostly tissuecidal
-Luminicidal effects are not reliable
-Used in combination with a luminicidal agent

DOC for Giardia ; DOC for Trichomonas

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Why does metronidazole not work well on Entamoeba histolytica in the GI lumen?

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because it's absorbed in other parts of the GI tract, and since the bugs are in the colon, there won't be any drugs to kill the bugs

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Metronidazole AE

compared to tinidazole

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Common: Nausea, metallic taste, headache
Infrequent : Vomiting, vertigo, insomnia, dizziness
Rare: Neuropathy – ataxia, encephalopathy, seizures

Disulfiram-like effects
Some evidence may be teratogenic (Avoid in 1st trimester)
Red-brown urine

*Tinidazole – same side effects, but better tolerated

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iodoquinol has iodine...duh. but if you take too much of this, what can you get? what is it good for? pharmacokinetics?

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iodine toxicity.

Luminal amebocide ONLY
Kills trophozoites and cysts in gut

-not absorbed very well orally

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Clinical use of Iodoquinol

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Asymptomatic amebiasis
Symptomatic intestinal amebiasis or with extraintestinal infections
--In combination with a tissuecidal agent (eg. metronidazole or tinidazole)

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Iodoquinol AE

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Anorexia, nausea, vomiting, diarrhea, abdominal cramps, pruritus ani
Iodine toxicity (Fever, itching, dermatitis)
Thyroid enlargement and altered thyroid function tests

Subacute myelo-optic neuropathy (SMON)
-Rare
-Muscle pain, weakness, optic atrophy (possibly vision loss), and
-ataxia
-Can be irreversible
-Usually occurs at high doses
-Children more susceptible
*Related to dose and duration of therapy!

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Paromomycin (Humatin) MoA, clinical use

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-An aminoglycoside!
-Not sure how it works as antiparasite
-Maybe it kills off gut bacteria, which is food for Entamoeba
-Luminal amebocide ONLY

almost no absorption, so 100% goes out into the feces

Asymptomatic amebiasis
Symptomatic intestinal amebiasis or with extraintestinal infections
--In combination with a tissuecidal agent (eg. metronidazole or tinidazole)

Similar to Iodoquinol

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Paromomycin AE

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Has the potential for all the aminoglycoside toxicities, but when used orally, there are only slight problems

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Nitazoxanide (Alinia) MoA, Clinical use (DOC for what?)

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-Exact MOA unclear!
-Appears to interfere with pyruvate-ferredoxin oxidoreductase (PFOR) dependent electron transfer reactions
-But does not appear to produce DNA mutations

DOC Giardia (along with metronidazole)
DOC Cryptosporidium (in non-HIV infected patients)

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If you have adult worms in the gut, what do you do? if you have adult worms or developmental forms in organs or tissues, what do you do?

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gut---> act locally to expel

organs/tissues--> act systemically to eradicate

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What are the three points of attack against them worms?

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Neuromuscular coordination
-Needed for feeding and attachment to host

Carbohydrate metabolism
-Energy source

Microtubular integrity for:
-Egg laying and hatching
-Glucose transport, enzyme activity, and secretion

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Benzimidazoles (BZAs) Agents

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Thiabendazole (Mintezol)
Mebendazole (Vermox)
Albendazole (Albenza)

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Benzimidazoles (BZAs) MoA

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-Binds b-tubulin thereby inhibiting microtubule polymerization
-Prevents microtubule dependent uptake of glucose
-Decreases ATP production, causing energy depletion, immobilization, and, finally, death

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Benzimidazoles pharmacokinetics, clinical use

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Mebendazole
-Limited oral absorption

Albendazole
-Poorly absorbed except, eating fatty meal enhances absorption up to 5 fold

Thiabendazole
-Well absorbed orally

Clinical use: Nematodes or roundworms

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Mebendazole and Albendazole clinical use (DOC for what?)

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DOC for many roundworms!!!
Trichuris trichiura (whipworms)
Ascaris lumbricoides
Necator and Ancylostoma (hookworms)
Enterobius vermicularis (pinworms)
Cutaneous lava migrans
Visceral larva migrans

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Albendazole clinical use

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Alternative for Strongyloides (threadworm)!! the others drugs aren't good for threadworms b/c they replicate in the host)

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Mebendazole and Albendazole Adverse effects

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Few adverse effects
-Poorly absorbed
Possibly teratogenic
-Contraindicated pregnancy

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thaibendazole clinical use, adverse effects

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Fairly broad spectrum, but toxicity limits its use to:
Strongyloides (threadworm)
Trichinosis
Cutaneous larva migrans (topically)

Anorexia, nausea, vomiting
CNS
-Dizziness, disturbed color vision, Hallucinations, Seizures
Hepatotoxic (Very rare)
Teratogenic potential
Stevens-Johnson syndrome (Rare)
Smells like asparagus

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Pyrantel pamoate (Ascarel, Pin-X) MoA

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depolarizing neuromuscular blocker

activates nicotinic receptor on muscle cell. sodium fluxes in causing a depolarization. however, if that receptor stays open all the time, there is bad contraction/relaxation (spastic paralysis).

it also inhibits AChesterase so you have more ACh to activate the nicotinic receptor

If you have this paralysis blockade, that means the worm can't move anymore, so it dies.

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Pyrantel pamoate clinical use...DOC for what..

adverse effects...

who is it useful for?

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Broad spectrum
Useful for some roundworms
DOC for Enterobius vermicularis (pinworms)
DOC for Necator and Ancylostoma (hookworms)
Ascaris lumbricoides – not a drug of choice

Quaternary nitrogen compound
Poorly absorbed from GI tract
Some CNS
-Headache and dizziness
NO evidence of teratogenesis
-Useful alternative in pregnancy

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Praziquantel (Biltricide) MoA

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Unclear
Effect on Schistosoma is understood the best (Schistosoma = blood fluke)

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Praziquantel how does it kill perhaps? DOC for what? AE?

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-> Increase membrane permeability to calcium -> Initial tetanicparalysis contraction AND immobilization of their suckers-> worms detach from the wall of the vein and the worm dies
or
vacuolization and subsequent disintegration of the tegument and the worms die.
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DOC for all tapeworms and flukes including schistosomes
--
Abdominal pain and nausea
Minor CNS effects (Headache & dizziness)
Avoid in pregnancy (Not teratogenic, Increases rate of abortion)

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Ivermectin (Stromectol)..how does it work

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glutamate gated chloride channel in the worm. hyperpolarization, paralysis, death.

-Binds with high affinity to glutamate-gated chloride channels in nematode muscle cells
-Leads to an increase in the permeability of the cell membrane to chloride ions, which hyperpolarizes the cell
-Causes paralysis and death of the parasite
-It also appears to interact with other ligand-gated chloride channels, such as those gated by g-aminobutyric acid (GABA)

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Ivermectin is the DOC for what? AE?

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**DOC for Strongyloides (threadworm)
DOC for Ascaris lumbricoides
DOC for cutaneous larva migrans
Alternative for Trichuris trichiura
**DOC for onchocerciasis – the filarial infection responsible for river blindness

AE:
Does not cross BBB very well (Does not affect host CNS function)
Possibly teratogenic (Contraindicated pregnancy)
Mazzotti-like reaction (during river blindness)
-Inflammatory or allergic response to dying microfilariae
-Intense itching, enlargement and tenderness of lymph nodes, rash, fever, tachycardia, arthralgias and headache