Anti-helminthic Agents Overview

Anti-helminthic Agents & Drugs Used for Treatment of Ectoparasitic Infections

• Helminths are worms that invade human hosts.
• Three types of helminths are nematodes (roundworms), trematodes (flukes), and cestodes (tapeworms).
• Anthelmintics act locally within the GI tract to expel worms or systemically against helminths outside the GI tract.

Learning Objectives

• Describe the therapeutic uses of antihelmintic and ectoparasitic drugs.
• Understand the mechanisms of action of antihelmintic and ectoparasitic drugs.
• Identify the toxicities and contraindications of antihelmintic and ectoparasitic drugs.

Introduction

• Helminths are worms that invade human hosts.
• Types of helminths: nematodes (roundworms), trematodes (flukes), and cestodes (tapeworms).
• Anthelmintics act locally within the GI tract to cause expulsion of worms or systemically against helminths residing outside the GI tract.
• Treatment of loiasis or onchocerciasis may cause tissue damage in large parasite burdens due to destruction of the microfilariae.

Anthelmintic Spectra

• Agent: Mebendazole, Praziquantel, Piperazine, Diethylcarbamazine, Levamisole, Ivermectin
• Susceptible Organisms: Pinworms, roundworms, whipworms, hookworms, flukes, roundworms, pinworms, roundworms, roundworms, roundworms

Praziquantel (Biltricide)

• Effective against cestode (tapeworm) and trematode (fluke) infections.
• Mechanism of action: Paralysis of the worm due to increased cell membrane permeability of calcium, targeting the tegument (skin equivalent), increasing calcium influx, increasing muscle contraction, and eventually causing paralysis followed by death. At higher doses, it releases antigens that stimulate a host immune response.
• Most effective against blood fluke infections (schistosomiasis), intestinal and liver fluke infections, and lung fluke infections (paragonimiasis).
• Side effects: Abdominal pain, nausea, diarrhea, headache, dizziness, drowsiness (no driving or operating machinery), and serious/rare CNS effects (seizures, intracranial hypertension, in neurocysticercosis). Also, inflammatory reactions to dead parasites. Corticosteroids may be co-administered to reduce inflammation.

Benzimidazoles

• Mechanism of action: Binds to β-tubulin to inhibit polymerization and microtubule assembly, impairing glucose uptake by nematodes, decreasing ATP production, and thus immobilizing the intestinal parasite. Cleared from the GI tract. Structural differences in β-tubulin between humans and parasites and mutations in β-tubulin prevent drug binding.
• Used to treat cysticercosis and cystic hydatid disease.
• Indications: Roundworm infections (Ascaris lumbricoides, Capillaria philippinensis, Enterobius vermicularis, Necator americanus, Trichuris trichiura), cestodes (E. granulosus and E. multilocularis).
• Side effects: GI distress, agranulocytosis, alopecia, teratogenic in animals. Thiabendazole has a wide nematode spectrum but limited clinical use due to toxicity.

Ivermectin (Mectizan)

• Mechanism of action: Tonic paralysis of nematode musculature. Binds to glutamate-activated Cl- channels in nerve or muscle cells, leading to hyperpolarization from increased intracellular chloride concentration. Ivermectin has no effect on adult parasites, but blocks egress of microfilariae from the uterus of female worms and effects developing larvae.
• Indications: Drug of choice for oral treatment of onchocerciasis, lymphatic filariasis, tropical pulmonary eosinophilia (caused by W. bancrofti and Brugia malayi). Drug of choice for human strongyloidiasis. Effective as diethylcarbamazine (DEC) for controlling lymphatic filariasis. Useful in regions where onchocerciasis, loiasis are endemic.
• Pharmacokinetics: Lipophilic, widely distributed, long elimination half-life (55-60 hours), excreted in feces. Absorption may be impaired in patients with disseminated strongyloidiasis. P-glycoprotein efflux pump in the brain reduces Ivermectin penetration into CNS, causing rare CNS side effects in humans.
• Side effects: Well-tolerated by uninfected humans. In onchocerciasis, destruction of microfilariae can cause reactions. In filarial infection, Mazzotti-like reaction to dying microfilariae. Not approved for use in children younger than 5 years or pregnant women.

Other Anthelminthic Drugs

• Diethylcarbamazine (Hetrazan): Decreases microfilariae muscular activity, causing dislocation; disrupts membranes, making them susceptible to host defense mechanisms. Drug of choice for Loiasis, Lymphatic filariasis, and Tropical pulmonary eosinophilia.
• Pyrantel pamoate (Antiminth): Selectively produces depolarizing neuromuscular blockade and inhibition of acetylcholinesterase (AChE) in the worm. Causes paralysis and flashes out intestinal nematodes. Useful in roundworm, hookworm, and pinworm.
• Piperazine (Vermizine): Blocks response to acetylcholine, altering parasite membrane permeability. Causes paralysis through neuromuscular junction stimulation of γ-aminobutyric acid (GABA). Effective against ascariasis and enterobiasis. Well absorbed from GI tract. Side effects include urticaria and bronchospasm as well as rare CNS effects (dizziness, paresthesia, vertigo, incoordination).
• Levamisole blocks nicotinic receptors at neuromuscular juntion. Niclosamide interferes with oxidative phosphorylation or activates ATPases. Levamisole and Niclosamide are used for Diphyllobothrium latum. Bithionol is an alternative to praziquantel for Fasciola hepatica and acute pulmonary paragonimiasis. Inhibits parasite respiration.

Drug Therapy of Scabies and Pediculosis

• Benzyl Benzoate: Efficient acaricide and drug of choice. Applied as an emulsion. Slight irritant and unpleasant odor. Effective against pediculosis but not recommended due to weak ovicidal activity and short duration of action.
• Ivermectin: Repeat dose after two weeks for ~95% cure.
• Monosulphiram: Acaricide solution/incorporated into soap. Recommended for scabies prophylaxis. Mild irritation, related to disulfiram.
• Crotamiton: Lotion/cream
• Permethrin: Synthetic pyrethroid cream/lotion. Pediculocide with residual effect for two weeks. Preferred over benzene hexachloride (GBH). May cause local reactions.
• Malathion: Pediculocidal and ovicidal organophosphorus compound (for head lice). Well tolerated, applied and left in for 8-12 hours, repeated 7 days later. Inflammable because of alcohol base.
• DDT: Pediculocide dusting powder (dicatione). Prolonged residual effect lethal to larvae hatching later. Bad odor, inflammable. Permethrin is preferred for initial treatment of pediculosis capitis. In resistant cases, ivermectin is safe and highly effective.

Clinical Scenario

• During a colonoscopy on an 80-year-old Filipino woman, a live worm was found.
• The gastroenterologist inquired about the patient's time in the United States.
• This information tells about the likely cause and effectiveness of the treatment.

Answer to Scenario

• Schistosomiasis is the most probable diagnosis given the patient's geographic origin.
• Praziquantel is used to treat this flatworm, but it is not effective in early schistosomiasis infections.
• If the patient has been in the US for a while, their infection is less likely. Treatment is likely to be effective immediately.