drug treatment of parasitic infections jf regal april 24, 2009 medical school duluth

Drug Treatment of Parasitic Infections

JF RegalApril 24, 2009

Medical School Duluth

Parasites

Protozoal Diseases LecturesMalaria ICMIntestinal Protozoal diseases GITropical and Sub-tropical Protozoa ICM

Helminth InfectionNematodes

Intestinal Roundworms GITissue Roundworms ICM

Trematodes or Flukes GICestodes or Tapeworms GI

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.

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

ProtozoaSingle cells

HelminthMulticellular

Parasites

Summary of Protozoal Disease Treatment

Metronidazole Tinidazole

Reduction of drug liberates toxic intermediates which damage DNA

Species difference in redox system

Iodoquinol Unknown Selective distribution; loss of visual acuity

Nitazoxanide Interferes with pyruvate:ferredoxin oridoreductase enzyme dependent electron transfer; essential for anaerobic metabolism

Species difference in electron transfer

Paromomycin Aminoglycoside mechanism Selective distribution Species difference in ribosomes

Tetracycline Tetracycline mechanism Selective distribution Species difference in ribosomes

Trimethoprim-sulfamethoxazole

Folate inhibitor Species difference in enzymes

Intestinal protozoa

Entamoeba histolytica Giardia lamblia Cryptosporidium parvum Balantidium coli Isospora belli

Pyrimethamine- Sulfadiazine


Other protozoa

Babesia spp Toxoplasma gondii Trichomonas vaginalis Pneumocystis jiroveci

Various Antibacterial drugs

Mechanism Selectivity

Arsenicals (melarsoprol)

Bind to –SH, principally trypanothione, a substitute for glutathione in trypanosomes

Selective accumulation

Liposomal amphotericin B

Ergosterol binding with pore formation

Species difference in sterols

Nifurtimox Generates reactive oxygen species which cause damage

Unknown

Miltefosine Unknown; maybe protein kinase C inhibitor or phosphatidylcholine synthesis inhibitor

Unknown

Organic antimonials (Sodium stibogluconate, Meglumine antimonate)

Interferes with glycolysis and fatty acid beta-oxidation; interfere with trypanothione redox system

Unknown

Pentamidine Hypothesized to interfere with kinetoplast DNA replication as a type II topoisomerase inhibitor

Species difference in enzymes

Tissue Protozoa (Tropical and sub-tropical protozoa)

Leishmania Trypanosoma brucei gambiense or rhodesiense Trypanosoma cruzi

Suramin Unknown Selective accumulation

Summary cont.

Chemotherapy of Protozoal Infections

Protozoal Diseases Protozoans are unicellular organisms with a nucleus and cytoplasm.

Two major protozoal diseases are:Plasmodium – malariaEntamoeba – amebiasis

Infecting organism Drug of Choice Alternative

Entamoeba histolytica Asymptomatic cyst passer Iodoquinol or

paromomycin Diloxanide

Intestinal disease Metronidazole followed by Paromomycin or Iodoquinol

Tinidazole

Hepatic abscess Metronidazole followed by Paromomycin

Balantidium coli Tetracycline Metronidazole

Cryptosporidium parvum Nitazoxanide

Dientamoeba fragilis Iodoquinol Tetracycline

Giardia lamblia Tinidazole or Nitazoxanide Metronidazole

Isospora sp. (coccidiosis) Trimethoprim-

Sulfamethoxazole

Pneumocystis jiroveci Trimethoprim- Sulfamethoxazole

Toxoplasma gondii Pyrimethamine plus Sulfadiazine

Trichomonas vaginalis Metronidazole

Luminal amebicide

Tissue amebicide

Entamoeba histolytica

Asymptomatic cyst passerTreated only with a luminal

amebicide• Iodoquinol or paromomycin

Intestinal disease and hepatic abscessTreated with tissue amebicide

followed by a luminal amebicide•Metronidazole (tissue)• Iodoquinol or paromomycin (lumen)

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.

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





Tinidazole







Sulfamethoxazole




Luminal amebicide

Tissue amebicide

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

Metronidazole

Headache, nausea, dry mouth and a metallic taste; potentially neurotoxic

Disulfiram reaction possibleAbdominal distress, vomiting,

flushing or headache with consumption of alcohol

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

Tetracycline

Incompletely absorbed Not for use in children or during

pregnancy Alters intestinal flora that is

essential for proliferation of the amoeba





Tinidazole







Sulfamethoxazole




Used in Immunocompromised No treatment in healthy individuals

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





Tinidazole







Sulfamethoxazole




Pyrimethamine orTrimethoprim

Sulfadiazine orSulfamethoxazole

Probably act on both the protozoa and the intestinal flora





Unknown


Unknown



Unknown






Tropical and Sub-tropical Protozoa

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

Infecting Organism Drug of Choice Alternative Leishmaniasis Miltefosine


Pentamidine or Sodium stibogluconate or

Meglumine antimonate African Trypanosomiasis Trypanosoma brucei gambiense or T. brucie rhodesiense

Hemolymphatic stage Pentamidine Suramin Late disease with central

nervous system involvement

Melarsoprol

Suramin + Melarsoprol

South American Trypanosomiasis (Chagas' disease) Trypanosoma cruzi Nifurtimox Benznidazole

More toxic drugs working at more difficult sites. Selective distribution in the GI tract does not work.

Organic antimonialsLeishmania and macrophages

Sodium stibogluconateMeglumine 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

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

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)

Infecting Organism Drug of Choice Alternative Leishmaniasis Miltefosine


Pentamidine or Sodium stibogluconate or

Meglumine antimonate African Trypanosomiasis Trypanosoma brucei gambiense or T. brucie rhodesiense

Hemolymphatic stage Pentamidine Suramin Late disease with central

nervous system involvement

Melarsoprol

Suramin + Melarsoprol

South American Trypanosomiasis (Chagas' disease) Trypanosoma cruzi Nifurtimox Benznidazole

More toxic drugs working at more difficult sites. Selective distribution in the GI tract does not work.

PentamidineT. 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

Suramin Unknown mechanism Does not penetrate the CNS appreciably Selectively accumulates in trypanosome

vs host Quite toxic

nausea, vomiting, shock, loss of consciousness

peripheral neuropathyphotophobiaurticariapruritisnephrotoxicity

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.

NifurtimoxT. 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

Summary of Protozoal Disease Treatment

Metronidazole Tinidazole

Reduction of drug liberates toxic intermediates which damage DNA

Species difference in redox system

Iodoquinol Unknown Selective distribution; loss of visual acuity

Nitazoxanide Interferes with pyruvate:ferredoxin oridoreductase enzyme dependent electron transfer; essential for anaerobic metabolism

Species difference in electron transfer

Paromomycin Aminoglycoside mechanism Selective distribution Species difference in ribosomes

Tetracycline Tetracycline mechanism Selective distribution Species difference in ribosomes

Trimethoprim-sulfamethoxazole


Intestinal protozoa

Entamoeba histolytica Giardia lamblia Cryptosporidium parvum Balantidium coli Isospora belli

Pyrimethamine- Sulfadiazine


Other protozoa

Babesia spp Toxoplasma gondii Trichomonas vaginalis Pneumocystis jiroveci

Various Antibacterial drugs

Mechanism Selectivity





Ergosterol binding with pore formation

Species difference in sterols


Unknown


Unknown



Unknown






Summary cont.

ProtozoaSingle cells

HelminthMulticellular

Parasites

Chemotherapy of Helminth Infections

Phylum NemathelminthesNematodes or roundworms

Ascaris, whipworm, pinworm, hookworm, trichinosis

Phylum PlatyhelminthesCestodes or tapeworms Trematodes including flukes (schistosomes)

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.

Two effective targets

Mechanisms essential for motor activity

Reactions that generate metabolic energy

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.

HELMINTHIC DISEASES AND TREATMENT Albendazole Mebendazole

Inhibits tubulin polymerization and microtubule formation

Species difference in tubulin Selective distribution

Ivermectin Paralysis by potentiating GABA-mediated signal transmission or by activating glutamate-gated chloride channels

Unknown

Intestinal Nematodes

(Roundworms)

Ascaris spp (roundworm) Trichuris spp (whipworm) Enterobius

vermicularis (pinworm)

Ancylostoma duodenale (hookworm)

Necator americanus (hookworm)

Strongyloides stercoralis

Pyrantel pamoate Binds to the nicotinic receptor and causes spastic paralysis of the worm

Species differences in receptors; selective distribution

Diethylcarbamazine Immobilizes microfilaria

Unknown Tissue

Nematodes (Roundworms)

Wuchereria bancrofti Brugia malayi Loa loa Onchocerca volvulus

Ivermectin Paralysis as above

Unknown

Helminthic Disease Treatment

GI

HELMINTHIC DISEASES AND TREATMENT Trematodes (flukes)

Schistosoma spp Clonorchis sinensis Fasciola hepatica Fasciolopsis buski Heterophyes heterophyes Metagonimus yokogawai Opisthorchis viverrini Paragonimus westermani

Praziquantal Contracts and dislocates worm by increasing calcium permeability; tegumental damage

Species difference in receptors

Albendazole Inhibits tubulin polymerization

and microtubule formation

Species difference in tubulin

Cestodes (tapeworms)

Diphyllobothrium latum Echinococcus granulosis Taenia spp

Praziquantal Contracts and dislocates worm by increasing permeability to calcium; tegumental damage


GI

Helminthic Disease Treatment

Infecting Organism Drug of Choice

Intestinal roundworms

Ascaris lumbricoides Mebendazole or Enterobius vermicularis (pinworm) Pyrantel Pamoate or Ancylostoma duodenale (hookworm) Albendazole Necator americanus (hookworm) Strongyloides stercoralis Ivermectin or Albendazole Trichuris trichiura (whipworm) Albendazole or Mebendazole Tissue roundworms Wuchereria bancrofti Diethylcarbamazine or Ivermectin Brugia malayi Diethylcarbamazine or Ivermectin Loa loa Diethylcarbamazine or Ivermectin Onchocerca volvulus Ivermectin (not diethylcarbamazine)

Nematode or Roundworm Infections

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

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

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

Infecting Organism Drug of Choice

Intestinal roundworms

Ascaris lumbricoides Mebendazole or Enterobius vermicularis (pinworm) Pyrantel Pamoate or Ancylostoma duodenale (hookworm) Albendazole Necator americanus (hookworm) Strongyloides stercoralis Ivermectin or Albendazole Trichuris trichiura (whipworm) Albendazole or Mebendazole Tissue roundworms Wuchereria bancrofti Diethylcarbamazine or Ivermectin Brugia malayi Diethylcarbamazine or Ivermectin Loa loa Diethylcarbamazine or Ivermectin Onchocerca volvulus Ivermectin (not diethylcarbamazine)

Nematode or Roundworm Infections

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.

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.

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












Flukes and Tapeworms

Infecting organism Drug of Choice Flukes (Trematodes) Schistosoma haematobium Praziquantel Schistosoma japonicum Praziquantel Schistosoma mansoni Praziquantel Schistosoma mekongi Praziquantel Clonorchis sinensis (Chinese liver fluke) Praziquantel Fasciola hepatica (Sheep liver fluke) Triclabendazole Fasciolopsis buski (intestinal fluke) Praziquantel Heterophyes heterophyes (intestinal fluke) Praziquantel Metagonimus yokogawai (intestinal fluke) Praziquantel Opisthorchis viverrini (liver fluke) Praziquantel Paragonimus westermani (lung fluke) Praziquantel Tapeworms (Cestodes) Diphyllobothrium latum (fish tapeworm) Praziquantel Taenia saginata (beef tapeworm) Praziquantel Taenia solium (pork tapeworm) Praziquantel Hymenolepis nana (dwarf tapeworm) Praziquantel Echinococcus granulosus (hydatid cyst) Albendazole

Praziquantal

Mechanism of action involves an increased permeability of the parasite to divalent cations, particularly calciumRapid 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

Chemotherapy of Infection

Principles CoursePrinciples of Chemotherapy Inhibitors of Cell Wall SynthesisInhibitors of Protein and Nucleic Acid Synthesis

Respiratory Course Review of antibacterials Antifungals, antiviralsDrugs used in tuberculosis

Fluids and ElectrolytesUrinary tract infections and review of antibacterials

ICMAntiparasitic drugs including malaria

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?

drug treatment of parasitic infections jf regal april 24, 2009 medical school duluth

Documents

specific drug

damage dnaspecies difference

drug namesin bold

handoutthe drug list

major protozoal diseases

major toxicities

unicellular organisms

general category of