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Drug Treatment of Parasitic Infections

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1 Drug Treatment of Parasitic Infections
JF Regal April 24, 2009 Medical School Duluth

2 Parasites Protozoal Diseases Lectures Malaria ICM
Intestinal Protozoal diseases GI Tropical and Sub-tropical Protozoa ICM Helminth Infection Nematodes Intestinal Roundworms GI Tissue Roundworms ICM Trematodes or Flukes GI Cestodes or Tapeworms GI

3 Objectives Know 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 exam Summary tables on p. 3 (protozoa) and p. 9 (worms) of the handout

5 Parasites Protozoa Single cells Helminth Multicellular

6 Summary of Protozoal Disease Treatment
Mechanism Selectivity Paromycin: 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 Diseases Protozoans are unicellular organisms with a nucleus and cytoplasm. Two major protozoal diseases are: Plasmodium – malaria Entamoeba – 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 passer Treated only with a luminal amebicide Iodoquinol or paromomycin Intestinal disease and hepatic abscess Treated with tissue amebicide followed by a luminal amebicide Metronidazole (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 tract Effective only against intestinal form of the disease i.e. luminal amebicide Most serious side effect is loss of visual acuity and even blindness at higher doses.

12 Paromomycin Aminoglycoside
Minimal absorption after oral administration Luminal amebicide that is not effective against extraintestinal forms GI upset and diarrhea High potential for ototoxicity and nephrotoxicity if given parenterally

13 Luminal amebicide Tissue amebicide

14 Metronidazole Mechanism Tissue amebicide
Not adequate as a luminal (intestinal) amebicide because it does not always achieve adequate concentrations in the intestine Should not be used alone in asymptomatic cyst passer

15 Metronidazole Headache, nausea, dry mouth and a metallic taste; potentially neurotoxic Disulfiram reaction possible Abdominal 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 metronidazole May be better tolerated than metronidazole More expensive than metronidazole May be effective in patients with metronidazole-resistant trichomoniasis Trichomonas 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 pregnancy Alters intestinal flora that is essential for proliferation of the amoeba Incomplete absorption is why it’s effective against protozoa.

18 Used in Immunocompromised
No treatment in healthy individuals

19 Nitazoxanide Recently approved for use in children for Giardia and Cryptosporidium Interferes with pyruvate:ferredoxin oxidoreductase enzyme dependent electron transfer; essential for anaerobic metabolism DNA damaging radicals are not formed; free of potential mutagenic effects


21 Sulfadiazine or Sulfamethoxazole Pyrimethamine or Trimethoprim Probably act on both the protozoa and the intestinal flora

22 Tropical and Sub-tropical Protozoa

23 Tropical and Sub-tropical Protozoa
Tissue protozoa – serious diseases Leishmaniasis – Sandfly bite transmits parasite into bloodstream where it infects macrophages at various sites. Cutaneous Mucocutaneous Diffuse cutaneous Visceral Trypanosomes – 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 CNS Chagas 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 stibogluconate Meglumine antimonate Interferes with glycolysis and fatty acid beta-oxidation in leishmania with a net reduction in the generation of ATP and GTP More recent studies suggest that the drug interferes with the trypanothione (like glutathione) redox system Incidence of treatment failures is increasing and resistance occurs Fairly well tolerated initially, but toxicity increases over time Adverse effects can include coughing, vomiting, myalgia, arthralgia, EKG changes

26 Liposomal Amphotericin B
Only for visceral leishmaniasis Drug of choice for antimonial resistant organisms Only liposomal formulation shown to be effective Antifungal drug that binds to ergosterol to form pores in membranes Nephrotoxicity and infusion toxicity

27 Miltefosine Unknown mechanism; maybe inhibition of protein kinase C or phosphatidylcholine synthesis Vomiting and diarrhea in up to 60% of patients Promising 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 involvement Does not penetrate the CNS Mechanism 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 system Resistance can occur from altered drug uptake Can be quite toxic - Hypotension, tachycardia, vomiting, hypoglycemia Since 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 host Quite toxic nausea, vomiting, shock, loss of consciousness peripheral neuropathy photophobia urticaria pruritis nephrotoxicity

31 Arsenicals - Melarsoprol
First line drug used for sleeping sickness which has progressed to CNS involvement. Penetrates into CNS Mechanism 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, Albuminuria Resistance can occur from altered drug uptake.

32 Nifurtimox T. cruzi, Chagas disease
Mainly for Trypanosome cruzi which multiplies within cells Mechanism thought to be similar to nitrofurantoin; formation of reactive oxygen species resulting in cellular damage Most 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
Mechanism Selectivity

34 Summary cont.

35 Parasites Protozoa Single cells Helminth Multicellular

36 Chemotherapy of Helminth Infections
Phylum Nemathelminthes Nematodes or roundworms Ascaris, whipworm, pinworm, hookworm, trichinosis Phylum Platyhelminthes Cestodes or tapeworms Trematodes 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 host Differential 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.

40 Helminthic Disease Treatment

41 Helminthic Disease Treatment

42 Nematode or Roundworm Infections

43 Pyrantel Pamoate Depolarizing 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 cholinesterase Poorly 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 infections Resistance involves mutations in parasite tubulin

45 Mebendazole, Albendazole
Mebendazole interacts with mammalian tubulin but is more selective for the parasite tubulin. Mebendazole is embryotoxic Differences in absorption, spectrum of activity and kinetics Less absorption of mebendazole than albendazole Albendazole is variably absorbed

46 Nematode or Roundworm Infections

47 Tissue Roundworms Filariasis – 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 Ivermectin Produces a paralysis of the peripheral musculature of the parasite, possibly by potentiating GABA-mediated signal transmission or by activating glutamate-gated chloride channels. Well tolerated Transient side effects include itching, swollen lymph glands and rarely dizziness and postural hypotension Adverse effects may be due in part to the host response to destruction of microfilaria.

49 Diethylcarbamazine Immobilizes the microfilaria by an unknown mechanism Headache, malaise, weakness, nausea, vomiting Adverse 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

50 Flukes and Tapeworms


52 Praziquantal Mechanism of action involves an increased permeability of the parasite to divalent cations, particularly calcium Rapid contraction of the worm's musculature occurs and dislocates the organism Influx of calcium across the tegument causes tegumental damage Sedation, abdominal discomfort, fever, sweating, nausea, eosinophilia


54 Chemotherapy of Infection
Principles Course Principles of Chemotherapy Inhibitors of Cell Wall Synthesis Inhibitors of Protein and Nucleic Acid Synthesis Respiratory Course Review of antibacterials Antifungals, antivirals Drugs used in tuberculosis Fluids and Electrolytes Urinary tract infections and review of antibacterials ICM Antiparasitic 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 class Mechanism Differences amongst drugs in a class Major toxicities Major issues of distribution and elimination Try to put the bugs and drugs together when it makes sense Example: Ineffectiveness of aminoglycosides against anaerobes; What are the anaerobes? Penicillinase producing Staph; What drug would you use?

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