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 TreatmentGI

41. Helminthic Disease TreatmentGI

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?