Lecture 9: Antiparasitic Agents and Resistance in Chemistry

pre-antibiotic

Still antiparasitic agents in use from the_______________ era with low efficacy/high toxicity

eukaryotes

parasites are _______ which means selective toxicity hard to find/achieve

parasitic infections in endemic countries

1. high incidence of multiple infections and reinfection

2. lack of access to proper diagnostics

3. immunocompromised patient populations (malnutrition, HIV)

4. poverty, poor sanitation

side effects

There is social resistance to antiparasitic treatment because of what?

Chloroquine

Drug-concentrating mechanism unique to parasite

Pyrimethamine or trimethoprim-sulfamethoxazole

Folic acid pathway (parasite unable to use exogenous folate)

poverty and poor sanitation

almost all parasitic infections are product of:

Arsenicals, difluoromethylornithine

Inhibitor of trypanothione-dependentmechanisms for reducing oxidized thiol groups

Pyrantel pamoate, diethylcarbamazine

Interference with neuromediators unique to parasites

Ivermectin

Interacts with chloride channels, resulting in hyperpolarization of cells, paralysis, and death of parasites

Benzimidazoles

Interaction with tubulin unique to parasites

Pentamidine

Inhibition of topoisomerase II

Nitazoxanide

Inhibition of pyruvate ferredoxin oxidoreductase

plasmodium

chloroquine organism target ?

plasmodium or toxoplasma spp.

Pyrimethamine or trimethoprim-sulfamethoxazole organism target?

trypanosomes

Arsenicals, difluoromethylornithine organism target?

ascaris spp.

Pyrantel pamoate, diethylcarbamazine organism target?

filaria

ivermectin organism target?

many helminths

benzimidazoles organism target?

trypanosomes

pentamidine organism target?

cryptosporidium and giardia

nitazoxanide organism target?

hemoglobin

what do malaria parasites eat?

Heavy metals (arsenical andantimonial compounds)

Oxidation of sulfhydryl groups in essential enzymes of carbohydrate metabolism

Aminoquinoline analogs

Antimalarial effects (e.g., interfere with DNA replication, hemoglobin digestion)

Folic acid antagonists

Inhibit dihydropteroate synthase and dihydrofolate reductase

inhibitors of protein synthesis

Block peptide synthesis at level of ribosome

antiprotozoal agents

_______ ________ generally are targeted at nucleic acid synthesis, protein synthesis, and specific metabolic pathways in proliferating, young, growing cells.

antiprotozoal agents

heavy metals, aminoquinoline analogs, folic acid antagonists, DNA or RNA synthesis inhibitors

anthelminthic agents

benzimadazoles, tetrahydropyrimidine, avermectins, pyrazinoisoquinoline

benzimidazoles

Inhibit fumarate reductase; inhibit glucose transport; disrupt microtubular function

Tetrahydropyrimidine

Blocks neuromuscular action; inhibits fumarate reductase

Avermectins

Block neuromuscular action; hyperpolarize nerve and muscle cells

Pyrazinoisoquinoline

Calcium agonist; causes tetanic muscular contractions; causes tegumental disruption; provides synergy with host defenses

nonproliferation adult organisms

Most anthelmintic drugs are targeted at:

anthelminthic drug targets

neuromuscular function, carb metabolisms, microtubular integrity

neuromuscular functions

movement, maintaining location in host, feeding

carb metabolism

energy source

microtubular integrity

important for egg, larval development, glucose transport, enzyme activities