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
antimalarial, localizes to digestive vacuoles, may interfere with hemoglobin degradation or detoxification of metabolic products, may complex with paraside DNA, interfering with transcription and replication, poorest therapeutic:toxic ration of all antimalarial drugs, causes cinchonism producing tinnitus, temporary hearing loss, headache, nausea, vomiting, and visual disturbances, hypoglycemia due to quinine induced release of insulin, problematic if patient with severe malaria is already suffering from hypoglycemia as a result of the parasites consumption of blood glucose, generally not used for chemoprophylaxis, adminsterd by IV with close monitoring, works well against all species causing disease, some resistance in Asia
quinine
similar to quinine, well tolerated, used for prophylaxis and treatment, half life of 14 days, toxicity in some reports demonstrate severe neuropsychiatric reactions in 0.5% of patients receiving mefloquine for treatment, treatment doses are 3 to 5 times greater than prophylactic
mefloquine
antimalarial, activation by host metabolism, thought to interfere with mitochondrial electron transport as well as pyrimidine synthesis, until recently, only drug available having activity against hypnozoite liver forms for plasmodium vivax and plasmodium ovale, causes RBC lysis in patients with glucose-6-phosphate dehydrogenase deficiency, patients should be screened for G6PD deficiency before adminstering primaquine, drug of choice for treating dormant liver forms of plasmodium vivax and plasmodium ovale, adminstered following chloroquine treatment of acute plasmodium vivax of plasmodium ovale infection or after prophylaxis with chloroquine in individuals who have had substantial risk of exposure to these organisms, resistant strains have emerged emerged which require repeated therapy with increased dosage
primaquine
antimalarial, much longer half life, much better tissue distribution than primaquine, single dose as effective as 2 weeks of primaquine, better compliance, same problem with glucose 6 phosphatase deficiency
tafenoquine
antimalarial, combination of atovaquone and proguanil, highly efficacious in the treatment of plasmodium falciparum, as well as in prophylaxis, no resistance reported yet
malarone
tetracycline which can be used for both malaria prophylaxis and treatment, thought to inhibit the growth of plasmodium by disrupting protein synthesis, primarily used in prophylaxis, in combination with other drugs for other drugs in treatment for malaria, causes photosensitivity dermatitis (increased sensitivity to sunburn) and staining of teeth in children, contraindicated in children and pregnant women
doxycycline
tetracycline which can be used for both malaria prophylaxis and treatment, thought to inhibit the growth of plasmodium by disrupting protein synthesis, primarily used in prophylaxis, in combination with other drugs for other drugs in treatment for malaria, causes photosensitivity dermatitis (increased sensitivity to sunburn) and staining of teeth in children, contraindicated in children and pregnant women
doxycycline
antimalarial, extracted from chinese wormwood, approved in the USA in 2009 as combination artemether:lumefantrine therapy for the treatment of plasmodium falciparum infections, mechanism of action unknown buy may interact with iron, causes nausea and diarrhrea, active against all human malaria parasites including multidrug resistant strains of plasmodium falciparum
artemisinin derivatives
enterbous vermicularis causing pinworm, ascaris lumbricoides causing ascariasis, necator americanus causing hookwork, trichuris trichirua causing whipworm, strongyloides stercoralis causing strongyloidiasis, cestodes causing tapework infections flukes causing trematode infections
anthelmintics targets
inhbit mitosis in the parasite by benzimidazole compounds or cause paralysis of the parasite with ivermectin, pyrantel, pamoate, and praziquantel, exact mechanism and reasons for toxicity unclear, includes albendazole, mebendazole, thiabenzole, poorly soluble with little drug absorbed from the gut which is good to effect parasites, thiabendazole is more effeciently absorbed accounting for greater toxicity, adminsiterd on empty stomach used to treat luminal nematodes, may be adminstered after a fatty meal to increase absorption and act on tissue dwelling helmints like larval tapework infections and trichinosis, resistance has emerged in veterinary mediicne, but currently is not a problem in human medicine, thiabendazole has greater absorption causing greater toxicity like anorexia, nausea, and vomiting, CNS disturbances inlcluding delirium and hallucinations, albendazole and mebendazole causes primarily Gi disturbances, benzimidazoles are contraindicated during pregnancy and questions remain regarding its use in children under 2 years of age
benzimidazole - anthelmintics
anthelmintic used for ascariasis, pinworm, hookworm, and whipworm infections, single high dose of either is sufficiency to resolve infection, mebendazole can also be given as smaller doses over a three day period, passage of the immobilized or dead worms may require several days (yuck)
albendazole and mebendazole
anthelmintics, second line drug used in treatment of strongyloidiasis intestinal and tissue infection, topical preparation is used in the treatment of cutaneous larval migrans (creeping eruption) caused by the larval forms of dog and cat hookworms
thiabenazole
causes hyperpolarization in muscle cells resulting in paralysis, no effect on mamallian cells, adminstered orally, absorbed rapidly, wide tissue distribution, used in treating intestinal and extraintestinal infections, drug of choice for treating strongyloidiasis intestinal and extraintestinal infections, 1 dose has a 65-100% cure so 2 doses may be needed, immunosuppressed patients may need more, used in treating tissue dwelling nematoides including o. volvulus causing river blindness, l.loa causing eye worm and filarial worms, w. bancrofti and b malayi, no evidence for resistance patterns
ivermectin
antihelmintics - activates cholinergic nicotinic receptors in the somatic muscles of nematodes and therby produces a depolarizing neuromuscular blockade, no effect on neuromuscular function in humans, poorly absorbed from the GI tract, selective toxicity to intestinal nematodes, generally well tolerated, with occasional mild GI disturbances selective toxicity to intestinal nematodes, generally well tolerated with occasional mild GI disturbances, drug of choice for treating pinworm, single dose repeated again in two weeks, cure rates are greater than 95% a third dose at 4 weeks is recommended in some publications, treatment of the entire household is recommended
pyrantel pamoate
treats tapeworm/cestode and fluke/trematode infections, increases calcium permeability of the worm’s tegument causing depolarization, increased immune detection, induces spastic paralysis in trematodes, easily absorbed and well tolerated and consisits primarily of abdominal discomfort, headache, and dizziness, indirect effects related to the immune response to dying worms, may include fever, rash, arthralgia, and myagia, drug of choice for treating nearly all infections of man caused by tapewoms and flukes, flukes are treated with three doses in a single day, tapeworms treated with a single dose, cysticercosis treated with two weeks treatment, resisance in schistosomes are beginning to occur
praziquantel
