Presentation on theme: "Drug Treatment of Parasitic Infections"— Presentation transcript:
1 Drug Treatment of Parasitic Infections JF RegalApril 24, 2009Medical School Duluth
2 Parasites Protozoal Diseases Lectures Malaria ICM Intestinal Protozoal diseases GITropical and Sub-tropical Protozoa ICMHelminth InfectionNematodesIntestinal Roundworms GITissue Roundworms ICMTrematodes or Flukes GICestodes or Tapeworms GI
3 ObjectivesKnow drug names and general category of organisms that the drug is used for i.e. protozoa, roundworm, cestode (tapeworms), trematode (flukes) etc.Don't memorize the specific drug of first choice for each infecting organism.Understand the mechanism of action and the basis for selective toxicity for each of the anti-parasitic drugs.Know major toxicities and relevant aspects of drug distribution.
4 Drug Names In bold throughout the handout The drug list on p. 2 of the word handout will be covered on the ICM examSummary tables on p. 3 (protozoa) and p. 9 (worms) of the handout
6 Summary of Protozoal Disease Treatment MechanismSelectivityParomycin: just like the other aminoglycosides, except it stays in the gut. Good b/c that’s where the parasites are and this prevents the systemic side effects (nephrotoxicity and ototoxicity)
7 Summary cont.More serious disease: more serious treatments. Arsenic: blocks of glutathione. Amphotericin = nephrotoxicity
8 Chemotherapy of Protozoal Infections Protozoal DiseasesProtozoans are unicellular organisms with a nucleus and cytoplasm.Two major protozoal diseases are:Plasmodium – malariaEntamoeba – amebiasis
9 Luminal amebicide Tissue amebicide Entamoeba: ppl can be passing cysts, but not have any systemic disease. Iodoquinol or paromomycin can treat this. But, if the organism is in the wall of the gut then have to use metronidazole followed by iodoquinol or paromyocin b/c metronidazole doesn’t kill them in the lumen very well.
10 Entamoeba histolytica Asymptomatic cyst passerTreated only with a luminal amebicideIodoquinol or paromomycinIntestinal disease and hepatic abscessTreated with tissue amebicide followed by a luminal amebicideMetronidazole (tissue)Iodoquinol or paromomycin (lumen)
11 Iodoquinol Unknown mechanism Selective distribution – only 10% of the drug is absorbed so it works locally on the protozoa in the GI tractEffective only against intestinal form of the disease i.e. luminal amebicideMost serious side effect is loss of visual acuity and even blindness at higher doses.
12 Paromomycin Aminoglycoside Minimal absorption after oral administrationLuminal amebicide that is not effective against extraintestinal formsGI upset and diarrheaHigh potential for ototoxicity and nephrotoxicity if given parenterally
14 Metronidazole Mechanism Tissue amebicide Not adequate as a luminal (intestinal) amebicide because it does not always achieve adequate concentrations in the intestineShould not be used alone in asymptomatic cyst passer
15 MetronidazoleHeadache, nausea, dry mouth and a metallic taste; potentially neurotoxicDisulfiram reaction possibleAbdominal distress, vomiting, flushing or headache with consumption of alcohol
16 Tinidazole Mechanism and adverse effects are similar to metronidazole Treatment course with tinidazole is shorter in general than with metronidazoleMay be better tolerated than metronidazoleMore expensive than metronidazoleMay be effective in patients with metronidazole-resistant trichomoniasisTrichomonas vaginalis, which is sexually transmitted, is usually asymptomatic in men but cuases vaginal discharge and discomfort in women.
17 Tetracycline Incompletely absorbed Not for use in children or during pregnancyAlters intestinal flora that is essential for proliferation of the amoebaIncomplete absorption is why it’s effective against protozoa.
18 Used in Immunocompromised No treatment in healthy individuals
19 NitazoxanideRecently approved for use in children for Giardia and CryptosporidiumInterferes with pyruvate:ferredoxin oxidoreductase enzyme dependent electron transfer; essential for anaerobic metabolismDNA damaging radicals are not formed; free of potential mutagenic effects
23 Tropical and Sub-tropical Protozoa Tissue protozoa – serious diseasesLeishmaniasis – Sandfly bite transmits parasite into bloodstream where it infects macrophages at various sites.CutaneousMucocutaneousDiffuse cutaneousVisceralTrypanosomes – Transmitted by the bite of the assassin bug or tsetse fly, depositing the organism into the eye or the bloodstream.African sleeping sickness -T brucei moves from bloodstream and lymph nodes into CNSChagas disease, South American, Serious cardiomyopathy -T. cruzi
24 More toxic drugs working at more difficult sites More toxic drugs working at more difficult sites. Selective distribution in the GI tract does not work.
25 Organic antimonials Leishmania and macrophages Sodium stibogluconateMeglumine antimonateInterferes with glycolysis and fatty acid beta-oxidation in leishmania with a net reduction in the generation of ATP and GTPMore recent studies suggest that the drug interferes with the trypanothione (like glutathione) redox systemIncidence of treatment failures is increasing and resistance occursFairly well tolerated initially, but toxicity increases over timeAdverse effects can include coughing, vomiting, myalgia, arthralgia, EKG changes
26 Liposomal Amphotericin B Only for visceral leishmaniasisDrug of choice for antimonial resistant organismsOnly liposomal formulation shown to be effectiveAntifungal drug that binds to ergosterol to form pores in membranesNephrotoxicity and infusion toxicity
27 MiltefosineUnknown mechanism; maybe inhibition of protein kinase C or phosphatidylcholine synthesisVomiting and diarrhea in up to 60% of patientsPromising treatment for leishmaniasis especially where resistance to antimonials is a problem (India)
28 More toxic drugs working at more difficult sites More toxic drugs working at more difficult sites. Selective distribution in the GI tract does not work.
29 Pentamidine T. brucei, extracellular Used in early trypanosomiasis before CNS involvementDoes not penetrate the CNSMechanism of action is thought to be interference with kinetoplast DNA replication as a type II topoisomerase inhibitor. A kinetoplast is a specialized structure in the trypanosome which is part of the mitochondrial systemResistance can occur from altered drug uptakeCan be quite toxic - Hypotension, tachycardia, vomiting, hypoglycemiaSince it doesn’t penetrate CNS, don’t use in late stages of Sleeping sickness
30 Suramin Unknown mechanism Does not penetrate the CNS appreciably Selectively accumulates in trypanosome vs hostQuite toxicnausea, vomiting, shock, loss of consciousnessperipheral neuropathyphotophobiaurticariapruritisnephrotoxicity
31 Arsenicals - Melarsoprol First line drug used for sleeping sickness which has progressed to CNS involvement.Penetrates into CNSMechanism of action probably involves sulfhydryl binding. The principal target is believed to be trypanothione, a substitute for glutathione in trypanosomes. Trypanothione maintains a reducing environment intracellularly and this is upset in the presence of melarsoprol.Very toxic - Encephalopathy, Fever, Hypertension, Vomiting, AlbuminuriaResistance can occur from altered drug uptake.
32 Nifurtimox T. cruzi, Chagas disease Mainly for Trypanosome cruzi which multiplies within cellsMechanism thought to be similar to nitrofurantoin; formation of reactive oxygen species resulting in cellular damageMost effective in acute stages and ineffective in chronic stages of the infection.Side effects are common; nausea, vomiting, myalgia, weakness, peripheral neuropathy
33 Summary of Protozoal Disease Treatment MechanismSelectivity
36 Chemotherapy of Helminth Infections Phylum NemathelminthesNematodes or roundwormsAscaris, whipworm, pinworm, hookworm, trichinosisPhylum PlatyhelminthesCestodes or tapewormsTrematodes including flukes (schistosomes)
37 Helminth Infections Multicellular organisms with crude organ systems Pathogenic forms of most of the worm infections amenable to chemotherapy are the adult, non-growing stages of the parasites life cycle.Growth inhibitors are not particularly useful.
38 Two effective targets Mechanisms essential for motor activity Reactions that generate metabolic energy
39 Strategies for selective toxicity Exploiting the biochemical differences between the parasite and hostDifferential distribution of the drug.The parasite is exposed to high concentrations of the drug in its intestinal habitat by the use of orally administered non-absorbable drugs.
43 Pyrantel PamoateDepolarizing neuromuscular blocker - binds to the nicotinic receptor causing depolarization and spastic paralysis of the worm. Paralyzed worms are then expelled from the intestine.Also inhibits cholinesterasePoorly absorbed (selective distribution)Causes nausea, vomiting, diarrhea
44 Mebendazole, Albendazole Binds to parasite tubulin and inhibits assembly of tubulin dimers into tubulin polymers. This causes a lack of formation of microtubules which are important in larval development, transport of carbohydrates (glucose uptake) and enzyme function.Good for treatment of multiple worm infectionsResistance involves mutations in parasite tubulin
45 Mebendazole, Albendazole Mebendazole interacts with mammalian tubulin but is more selective for the parasite tubulin. Mebendazole is embryotoxicDifferences in absorption, spectrum of activity and kineticsLess absorption of mebendazole than albendazoleAlbendazole is variably absorbed
47 Tissue RoundwormsFilariasis – caused by nematodes that inhabit the bloodstream or lymphatics and subcutaneous tissues as adults and microfilaria.Adverse effects of the drugs may be due in part to the host response to destruction of microfilaria.
48 IvermectinProduces a paralysis of the peripheral musculature of the parasite, possibly by potentiating GABA-mediated signal transmission or by activating glutamate-gated chloride channels.Well toleratedTransient side effects include itching, swollen lymph glands and rarely dizziness and postural hypotensionAdverse effects may be due in part to the host response to destruction of microfilaria.
49 DiethylcarbamazineImmobilizes the microfilaria by an unknown mechanismHeadache, malaise, weakness, nausea, vomitingAdverse effects may be due in part to the host response to destruction of microfilaria.Use in River Blindness (Onchocerca volvulus) increases risk of ocular side effects, including blindness, associated with rapid killing of the worms
52 PraziquantalMechanism of action involves an increased permeability of the parasite to divalent cations, particularly calciumRapid contraction of the worm's musculature occurs and dislocates the organismInflux of calcium across the tegument causes tegumental damageSedation, abdominal discomfort, fever, sweating, nausea, eosinophilia
54 Chemotherapy of Infection Principles CoursePrinciples of ChemotherapyInhibitors of Cell Wall SynthesisInhibitors of Protein and Nucleic Acid SynthesisRespiratory CourseReview of antibacterialsAntifungals, antiviralsDrugs used in tuberculosisFluids and ElectrolytesUrinary tract infections and review of antibacterialsICMAntiparasitic drugs including malaria
55 Board Study for Chemotherapy Combine the antibacterial, antifungal, antiviral and antiparasitic drugs and make sure you can put each name in a drug classMechanismDifferences amongst drugs in a classMajor toxicitiesMajor issues of distribution and eliminationTry to put the bugs and drugs together when it makes senseExample: Ineffectiveness of aminoglycosides against anaerobes; What are the anaerobes?Penicillinase producing Staph; What drug would you use?