25. Antiparasitic Agents Flashcards
parasitic worms are eukaryotic, identical or nearly identical cellular structures, metabolic pathways, and cellular machinery, so there are not that many truly unique targetsk
antiparasitic chemotherapy obstacle
infections caused by parasites are uncommon in the US when compared to bacterial and viral infections, those in the US generally cause limited morbidity and mortality, resulting in little drugs in R&D
social and economic obstacles of antiparasitic chemotherapy
enzymes or processes found only in the parasite, enzymes of processes found in both the host and parasite but indispensable only in the parasite, or common biochemical functions found in both the parasite and host, but with different pharmacologic properties
antiparasitic chemotherapy targets
intestinal and luminal infections like giardiasis, amebiasis, and trichomoniassi, opportuninistic infections like HIV/AIDS including cryptosporidiosis, toxoplasmosis, pneumocystis jirovecii, and pneumonia, and malaria prophylaxis and treatment
anti-protozal treatment areas
ameboid form and cyst form, causes amebic dyssentry but can leave the intestine and cause disseminated disease in the gut,
entameboa histolytica
has a motile trophozoite form or a cysted form in the gut
giardiasis
no cyst form, only needs to be cleared from the urogenital tract
trichomonas
giardia, entamoeba, and trichomonas are all anaerobic lumen swelling protozoans, all posses enztyme pyruvate ferredoxin oxidoreductase, similar to pyruvate dehydrogenase in aerobic organisms, PFOR catalyzes the conversion of pyruvate to Acetyl CoA, not present in humans, is a nitroimidazole compound acting as an electron skin within the cell, enters the cell in inactive form, activated/reduced under anaerobic conditions by PFOR, reactive intermediates form which bind to and disrupt protein and DNA structure and function, electrons are diverted from normal energy yielding pathways, adminstered orally, well absorbed, little evidence of host toxicity, causes headache, dry mouth, and metallic taste, vomiting, diarrhea, and abdominal distress are occasionally reported, disulfiram like effect to avoid alcohol consumption, considered safe for use during pregnancy, some sources discourage its use during the first trimester, trichomoniasis has a 1 day or 7 day regiment, is 90% successful at treating giardiasis, in amebiasis only kills trophozoite forms, is the frug of choice for treating symptomatic disease, follow this course of therapy with a more potent luminal amebicide like iodoquinol and paramomycin to eradicate non-invasive cyst forms, is effective in treating invasive intestinal disease as well as extraintestinal amebiasis like liver and brain abscesses, resistnance is rare but documented with increasing frequency in clinical isolates and laboratory maintained strains of trichomonas and giardiasis
metronidazole
halogenated hydroxyquinolone, poorly understood mechanism of action, effective at eliminating trophozoite and cyst forms of entamoeba histolytica from the lumen of the intestine, poorly absorbed at 10%, no activity against trophozoite forms in tissue like the intestine or others, causes GI discomfort, take with meals to avoid/reduce gastrointestinal toxicity, adminstration of high doses to children causes vision problems, used to treat asymptomatic or mild cases of amebiasis, in severe cases should be used following treatment with metronidazole, used in 20 day regiment, no information on resistance
iodoquinol
aminoglycoside antibiotic, inhibits protein synthesis in bacteria, mechanism of action is unknown, effective at eliminating both trophozoite and cyst forms for entamoeba histolytic from the lumen of the intestine, no activity against trophozoite forms that have invaded tissue like the intestines or other, used to treat asymptomatic or mild cases of amebiasis, used in severe cases following treatment with metronidazole, used for 7 days, no information on resistance
paromomycin
cryptosporidium parvum, pneumocystis jirovecii, toxoplasma gondii
AIDS patients opportunistic infections
large water borne outbreaks, profuse watery diarrhea, in healthy individuals infection is self limiting, treatment focuses on rehydration, in immunosuppressed patients, may be responsible for 25% of diarrhea in AIDS, may be chronic and fatal, treat with nitazoxanide, interferes with pyruvate derredoxin oxidoreductase, disrupts anaerobic energy metabolism, oral suspesion approved and indicated for treatment of crptosporidiosis and giardiasis in individuals 1+ years of age, no information regarding resistance
cryptosporidium parvum
inhibitors of folate synthesis, treats pneumocystis jirovecii and toxoplasma gondii, inhibits dihydropteroate synthase and dihydrofolate reductase, both are adminstered orally, well absorbed and rapidly distributed throughout the body, sulfonamides cause rash, crystalluria, gastrointestinal intolerance, and hemolysis, resistance reported in both organisms correlating with point mutations in targeted enzymes
trimethoprime sulfamethoxazole and pryimethamine sulfadiazine
most important parasitic diseases, 1-2 thousand cases diagnosed related to travel and immigration, chemotherapy includes prophylaxis and treatment, transmitted by bite of mosquite injecting sporozoite, replicates in the liver, goes to circulation, inhabits red blood cells causing symptoms, most drugs are aimed at targeting erythrocyte phase, some drugs eradicate liver forms for plasmodium vivax and plasmodium ovale
malaria
antimalarial, unclear, thought to interfere with parasitic ability to detocify compounds generated during degradation of hemoglobin, adminstered orally, half life in the body of 4 days, allows for a once weekly regiment of prophylaxis, higher doses of drug are adminstered 4 time sover a 48 hour period of 0, 6, 24, and 48 hours, causes include headache, nausea, vomiting, blurred vision, dizziness, fatigue, big time resistance so limited usefulness in many parts of the world
chloroquine
