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ANTHELMINTIC AGENTSANTHELMINTIC AGENTS

Assoc. Prof. Dr. Ferda Kaleağasıoğlu Department of Pharmacology

Faculty of Medicine, Yeditepe University

Anthelmintic Agents Lecture Outline

Introduction ◦ Nematode infections

◦ Cestodes infections

◦ Trematodes infections

Benzimidazoles ◦ Mebendazole

◦ Albendazole

◦ Thiabendazole

Diethylcarbamazine

Ivermectin

Pyrantel Pamoate

Praziquantel

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LearningLearning OutcomesOutcomes AnthelminticAnthelmintic AgentsAgents

Following this lecture you should be able to: describe the mechanism of action list the drugs used against nematode,

cestode and trematode infections define important aspects of

pharmacokinetics identify clinical uses list untoward reactions

Nematodes

Roundworms

Trematodes

Flatworms - flukes

Cestodes

Flatworms – tapeworms

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Human pathogen

Metazoa

Platyhelminthes (flatworms) Nemathelminthes

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ClassificationClassification NEMATODES CESTODES TREMATODES

Ascaris lumbricoides (roundworm) Taenia saginata (beef tapeworm) Schistosoma haematobium

Schistosoma mansoni

Schistosoma japonicum

Toxocara canis Taenia solium (pork tapeworm) Paragonimus

Necator americanus, Ancylostoma

duodenale (Hookworm)

Diphyllobothrium latum Clonorchis sinensis

Trichuris (whipworm) Hymenolepis nana Opisthorchis viverrini

Opisthorchis felineus

Strongyloides stercoralis

(threadworm)

Echinococcus species Fasciola hepatica

Enterobius vermicularis Fascolopsis buski

Trichinella spiralis

Wuchereria bancrofti

Brugia malayi

B. Timori

Loa loa

Onchocerca volvulus

Dracunculus medinensis

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WHO RECOMMENDATION

Periodic and frequent use of anthelminthic drugs in schools is

recommended for prevention of morbidity casued by STHs.

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NematodesNematodes

Elongated roundworms with a complete digestive system, including both a mouth and an anus.

They cause infections of the intestine as well as the blood and tissues.

Ascaris lumbricoides

NematodesNematodes

Soil transmitted helminths (STHs, geohelminths) ◦ Ascariasis (roundworm)

◦ Trichuriasis (whipworm)

◦ Necator americanus, Ancylostoma duodenale (hookworms)

◦ Enterobius vermicularis (pinworm)

◦ Strongyloides stercoralis

◦ Trichinella spiralis Filarial nematodes

◦ Wuchereria bancrofti

◦ Brugia malayi

◦ B. Timori

◦ Loa loa

◦ Onchocerca volvulus Dracunculus medinensis

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HowHow wormsworms movemove

Nematodes move in wave-like motions.

One segment contracts, then it “pulls” the body’s rest forward.

The contractions and relaxations provide the movement.

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Pathogen Drug of Choice

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Ascaris lumbrcoides

(roundworm)

Mebendazole, albendazole, pyrantel pamoate

Toxocara canis Albendazole

Necator americanus, Ancylostoma duodenale

(hookworm)

Albendazole

Trichuris (whipworm) Mebendazole, albendazole

Strongyloides stercoralis Ivermectin

Enterobius vermicularis (pinworm) Mebendazole, albendazole, pyrantel pamoate

Trichinella spiralis Mebendazole, albendazole

Wuchereria bancrofti, Brugia malayi, B. Timori DEC

Loa loa DEC

Onchocerca volvulus Ivermectin

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Taenia saginata &Taenia solium adult Niclosamide (albendazole, praziquantel)

Taenia solium larvae >>cysticercosis Praziquantel, albendazole

Diphyllobothrium latum Niclosamide

Hymenolepis nana Praziquantel

Echinococcus species Albendazole

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Schistosoma Praziquantel

Paragonimus Praziquantel

Clonorchis sinensis, Opisthorchis Praziquantel

Fasciola hepatica Triclabendazole

Fascolopsis buski Praziquantel

BenzimidazolesBenzimidazoles

Mebendazole

Albendazole

Thiabendazole

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MebendazoleMebendazole

Effective against a wide spectrum of nematodes.

Drug of choice in the treatment of ◦ roundworm (Ascaris lumbricoides)

◦ hookworms (Necator americanus Ancylostoma duodenale)

◦ pinworm (Enterobius vermicularis)

◦ whipworm (Trichuris trichiura)

MebendazoleMebendazole

Higher affinity for parasite b-tubulin than higher eukaryote’s b-tubulin.

Affected parasites are expelled by the feces.

Inhibition of microtubule

polymerization

Reduced glucose uptake

Uncoupling of oxidative

phosphorylation

ATP deprivation & death

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Microtubule: A major class of filaments of cytoskeleton

Tubulin: protein subunit of microtubules

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BenzimidazolesBenzimidazoles

Pharmacokinetics Mebendazole and albendazole ◦ Poorly soluble in aqueous solution.

◦ Low bioavailability: Poor absorption and rapid first-pass metabolism

Adverse Effects Mebendazole and albendazole ◦ Excellent safety profile

Thiabendazole ◦ Clinical use is compromised by its toxicity

◦ Anorexia, nausea, vomiting, dizziness

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BenzimidazolesBenzimidazoles

Treatment should be avoided during the first trimester of pregnancy.

Due to the risk of development of iron deficiency anemias in infected women, treatment would be beneficial during the second and third trimesters of pregnancy.

DiethylcarbamazineDiethylcarbamazine (DEC)(DEC)

MoA

Organelle damage and apoptosis; immobilize microfilaria

Clinical use

First line agent for the control and treatment of lymphatic filariasis ◦ kills microfilaria and

some of the adult worms

◦ Wuchereria bancrofti,

◦ Brugia malayi,

◦ B. Timori

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DiethylcarbamazineDiethylcarbamazine (DEC)(DEC)

Adverse effects are due to host reactions to the killed

organisms

◦ Symptoms: fever, malaise, rash, myalgias, arthralgias, and

headache,

severity is related to parasite load.

Most patients have leukocytosis.

Antihistamines or steroids may be given to ameliorate many of the symptoms.

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IIvermectinvermectin

MoA:

Activates glutamate –gated Cl-

channels (mostly expressed on

pharyngeal muscles)

hyperpolarization paralysis

feeding is disrupted

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Dent J A et al. PNAS 2000;97:2674-2679

©2000 by National Academy of Sciences

Ivermectin MoA

IIvermectinvermectin

Therapeutic uses:

• Onchocerciasis

• Strongyloidiasis

Onchocerciasis

River blindness

Lymphatic filariasis

Ivermectin kills only the microfilariae, but not

the adult worm which is responsible for the

pathology of lymphedema and hydrocele.

Annual (twice) mass treatment with

albendazole and ivermectin

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IvermectinIvermectin

Adverse effects

Mazzotti-like reaction ◦ Due to antigen burden

◦ lymphadenopathy

◦ tachycardia

◦ hypotension

◦ facial edema

◦ peripheral edema

◦ myalgia

◦ arthralgia

◦ encephalopathy

PyrantelPyrantel PamoatePamoate

MoA:

Depolarising neuromuscular blockage

Inhibiton of cholinesterases

Therapeutic uses

Ascariasis, enterobiasis

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PraziquantelPraziquantel

MoA:

Low C > spastic paralysis

High C > helminth damage

Therapeutic uses

Schistosomiasis

Some other trematode infestations

Schistosomiasis

Pathogen Drug of Choice

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Ascaris lumbrcoides

(roundworm)

Mebendazole, albendazole, pyrantel pamoate

Toxocara canis Albendazole

Necator americanus, Ancylostoma duodenale

(hookworm)

Albendazole

Trichuris (whipworm) Mebendazole, albendazole

Strongyloides stercoralis Ivermectin

Enterobius vermicularis (pinworm) Mebendazole, albendazole, pyrantel pamoate

Trichinella spiralis Mebendazole, albendazole

Wuchereria bancrofti, Brugia malayi, B. Timori DEC

Loa loa DEC

Onchocerca volvulus Ivermectin

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Taenia saginata &Taenia solium adult Niclosamide (albendazole, praziquantel)

Taenia solium larvae >>cysticercosis Praziquantel, albendazole

Diphyllobothrium latum Niclosamide

Hymenolepis nana Praziquantel

Echinococcus species Albendazole

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Schistosoma Praziquantel

Paragonimus Praziquantel

Clonorchis sinensis, Opisthorchis Praziquantel

Fasciola hepatica Triclabendazole

Fascolopsis buski Praziquantel

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Side Side EffectsEffects Agent Dose

Mebendazole Relatively free of toxic effects, although patients may complain of

abdominal pain and diarrhea; contraindicated in pegnancy

Albendazole Adverse effects are mild and transient and include headache and nausea.

Treatment of hydatid disease (3 months) has a risk of hepatotoxicity and,

rarely, agranulocytosis or pancytopenia; contraindicated in pegnancy

Thiabendazole

Dizziness, anorexia, nausea, and vomiting, central nervous system

symptoms, erythema multiforme and Stevens-Johnson syndrome;

contraindicated in pegnancy

Diethylcarbamazine

(DEC)

Adverse effects are primarily caused by host reactions to the killed

organisms. The severity of symptoms is related to the parasite load and

include anorexia, nausea, fever, malaise, rash, myalgias, arthralgias, and

headache. Most patients have leukocytosis

Ivermectin Well tolerated in uninfected. CNS effects, contraindicated in pegnancy

Praziquantel Common adverse effects include drowsiness, dizziness, malaise, and

anorexia, as well as gastrointestinal upsets. The drug is not recommended

for pregnant women or nursing mothers.

Pyrantel pamoate Mild and include nausea, vomiting, and diarrhea