Anthelmintic Drugs

Anthelmintic drugs are used to treat infections caused by parasitic helminths. Helminths include both flatworms (flukes and tapeworms) and roundworms. Anthelmintic medications are categorized on the basis of the class of helminths they are used for. Nematicidal agents include the benzimidazoles (albendazole, mebendazole, and triclabendazole), diethylcarbamazine, ivermectin, and pyrantel pamoate. Praziquantel is a trematocidal and cestodicidal agent. The mechanisms of action of the anthelmintic drugs vary, but many work by disrupting the normal function of the organism, inducing paralysis, and/or causing death. Most of these drugs are well absorbed, which can allow for treatment of systemic infections. Pyrantel pamoate, on the other hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand, is poorly absorbed and is better suited to treating luminal nematodes. The benzimidazoles’ absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption is changed by the presence of food, which allows for some control in treating luminal or invasive infections (such as cysticercosis). Adverse effects of anthelmintics vary, but all classes of these drugs are associated with GI side effects.

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Overview

Classification of helminths

The different classes of helminths are: 

  • Roundworms (nematodes)
  • Flatworms (platyhelminths):
    • Tapeworms (cestodes)
    • Flukes (trematodes)

Classification of anthelmintic drugs

The most commonly used anthelmintic drugs are: 

  • Nematicidal agents:
    • Benzimidazoles
    • Diethylcarbamazine 
    • Ivermectin
    • Pyrantel pamoate 
  • Trematocidal and cestodicidal agents: 
    • Praziquantel 
    • Niclosamide (discontinued in the United States)

Benzimidazoles

Medications in this class

  • Albendazole
  • Mebendazole
  • Triclabendazole

Mechanism of action

  • Bind to free beta-tubulin → prevent polymerization into microtubules
  • Effects:
    • ↓ Microtubule-dependent glucose uptake → ↓ ATP production → energy depletion 
    • Worm immobilization 
    • Disrupted reproduction
    • Death

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption:
    • Poorly absorbed orally
    • Absorption ↑ with food (fatty meals).
  • Distribution: highly protein-bound
  • Metabolism:
    • 1st-pass metabolism in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
    • Albendazole and triclabendazole have active metabolites.
  • Excretion: mostly in the feces

Indications

Albendazole and mebendazole have activity against a broad spectrum of: 

  • Nematodes:
    • Ascaris Ascaris Ascaris is a genus of parasitic nematodes. The infection, ascariasis, is most often caused by A. lumbricoides. Transmission occurs primarily via ingestion of water or food contaminated with Ascaris eggs. Most patients with ascariasis are asymptomatic. Ascaris/Ascariasis lumbricoides
    • Ancylostoma duodenale and A. caninum
    • Enterobius Enterobius Enterobiasis is a helminth infection caused by Enterobius vermicularis, also known as a pinworm. This infection is typically seen in children and is transmitted through the fecal-oral route. The primary clinical feature is anal pruritus, but patients are often asymptomatic. Enterobius/Enterobiasis vermicularis 
    • Necator americanus
    • Strongyloides stercoralis 
    • Toxocara Toxocara Toxocariasis is caused by the nematodes Toxocara canis and T. cati. These species frequently infect dogs and cats and are most commonly transmitted to humans via accidental ingestion of eggs through the fecal-oral route. Toxocara are not able to complete their life cycle in humans, but they do migrate to organs (including the liver, lungs, heart, brain, and eyes), where they cause inflammation and tissue damage. Toxocariasis species
    • Trichinella Trichinella Trichinellosis is an illness caused by infection with Trichinella. The most common causative parasite is Trichinella spiralis, which is usually found in pigs and transmitted to humans through the ingestion of undercooked meat. Once ingested, the parasite grows and matures within the intestinal walls. Symptoms occur during larval migration. Trichinella/Trichinellosis spiralis 
    • Trichuris trichina 
  • Trematodes:
    • Clonorchis sinensis (Chinese liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver fluke)
    • Opisthorchis viverrini (Southeast Asian liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver fluke)
  • Cestodes:
    • Echinococcus Echinococcus Echinococcosis is a parasitic disease caused by Echinococcus tapeworms. Infection most often occurs from the ingestion of Echinococcus eggs in food or water contaminated with dog feces. Signs and symptoms are caused by hydatid cyst development in visceral organs and depend on the species. Echinococcus/Echinococcosis granulosus (dog tapeworm)
    • Taenia Taenia Taenia belong to the Cestoda class of helminths. Humans are infected with these tapeworms by eating undercooked beef (T. saginata) or pork (T. solium and T. asiatica). Taeniasis is often asymptomatic, but the ingestion of larvae can cause abdominal discomfort, nausea, and constipation or diarrhea. Taenia/Taeniasis saginata (beef tapeworm) 
    • Taenia Taenia Taenia belong to the Cestoda class of helminths. Humans are infected with these tapeworms by eating undercooked beef (T. saginata) or pork (T. solium and T. asiatica). Taeniasis is often asymptomatic, but the ingestion of larvae can cause abdominal discomfort, nausea, and constipation or diarrhea. Taenia/Taeniasis solium (pork tapeworm) 
  • Others:
    • Giardia duodenalis
    • Microsporidia Microsporidia Microsporidia are a group of obligate intracellular organisms that were recently reclassified as fungi. The most common species of Microsporidia is Enterocytozoon bieneusi. Microsporidia species are ubiquitous, with a wide range of reservoirs. Immunocompromised individuals (particularly those with AIDS and a CD4 count < 100 cells/µL) most commonly develop symptomatic microsporidiosis. Microsporidia/Microsporidiosis

Adverse effects

  • Headache 
  • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Nausea and vomiting
  • ↑ Liver enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes 
  • Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia
  • Agranulocytosis

Diethylcarbamazine

Mechanism of action

  • Not completely understood
  • Works on microfilariae (early stage of certain nematodes, usually in the circulatory system or tissues):
    • Immobilizes
    • Alters surface structure → ↑ susceptibility to phagocytosis and destruction

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption:
    • Well absorbed
    • Rapid
  • Distribution: widely to most tissues (except adipose)
  • Excretion: urine (approximately 50% as unchanged drug)

Indications

Diethylcarbamazine is indicated for the following nematode infections:

  • Lymphatic filariasis Lymphatic filariasis Lymphatic filariasis, also known as elephantiasis, is a chronic mosquito-borne infection caused by Wuchereria bancrofti, Brugia malayi, and B. timori. The majority of causes are due to W. bancrofti. Mosquitos are the vectors, and humans are the primary reservoir. Patients with acute infection can present with fever, adenolymphangitis, dermatolymphangioadenitis, and tropical pulmonary eosinophilia. Lymphatic Filariasis (Elephantiasis) caused by: 
    • Wuchereria bancrofti
    • Brugia malayi
    • Brugia timori 
  • Loiasis (Loa loa)
  • Visceral larva migrans ( Toxocara Toxocara Toxocariasis is caused by the nematodes Toxocara canis and T. cati. These species frequently infect dogs and cats and are most commonly transmitted to humans via accidental ingestion of eggs through the fecal-oral route. Toxocara are not able to complete their life cycle in humans, but they do migrate to organs (including the liver, lungs, heart, brain, and eyes), where they cause inflammation and tissue damage. Toxocariasis spp.)

Adverse effects

  • Headache
  • Malaise
  • Anorexia
  • Nausea and vomiting
  • Reactions to dying microfilariae:
    • Fever
    • Rash
    • GI symptoms
    • Cough
    • Chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain
    • Swelling
    • Pruritus
    • Arthralgia and myalgia
    • Proteinuria
    • Encephalopathy

Ivermectin

Chemistry

  • Semisynthetic macrocyclic lactone 
  • Derived from avermectin (from the mold Streptomyces avermitilis)
  • Lipophilic

Mechanism of action

  • Selectively binds to glutamate-gated chloride ion channels 
  • ↑ Permeability of the cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane to chloride ions
  • Hyperpolarization → paralysis of organisms

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption:
    • Well absorbed
    • ↑ Absorption with high-fat meals
  • Distribution: 
    • High concentration in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or "brite" adipose tissue, which is a transitional form. Adipose Tissue 
    • Does not cross the blood–brain barrier 
    • Highly protein-bound
  • Metabolism: 
    • Hepatic
    • By cytochrome P450 enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
  • Excretion: mainly in feces

Indications

  • Nematodes:
    • Ascaris Ascaris Ascaris is a genus of parasitic nematodes. The infection, ascariasis, is most often caused by A. lumbricoides. Transmission occurs primarily via ingestion of water or food contaminated with Ascaris eggs. Most patients with ascariasis are asymptomatic. Ascaris/Ascariasis lumbricoides
    • Onchocerca volvulus Volvulus A volvulus is the twisting or axial rotation of a portion of the bowel around its mesentery. The most common site of volvulus in adults is the colon; most frequently the sigmoid volvulus. Patients typically present with symptoms of bowel obstruction such as abdominal pain, distension, vomiting, and constipation/obstipation. Volvulus (river blindness)
    • Strongyloides stercoralis
    • Wuchereria bancrofti infection (lymphatic filariasis)
  • Other: 
    • Prevention and control of scabies Scabies Scabies is an infestation of the skin by the Sarcoptes scabiei mite, which presents most commonly with intense pruritus, characteristic linear burrows, and erythematous papules, particularly in the interdigital folds and the flexor aspects of the wrists. Scabies infections
    • Pediculus humanus capitis (head lice)

Adverse effects

  • Dizziness
  • Nausea and vomiting
  • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Myalgias
  • Pruritus
  • Rash
  • Stevens-Johnson syndrome Stevens-Johnson syndrome Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome
  • Orthostatic hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Confusion
  • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures 
  • ↑ Liver enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes

Contraindications

  • Extreme caution in children: ↑ risk of CNS effects
  • Avoid in pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care

Drug interactions

Enhanced GABA activity may occur with:

  • Barbiturates
  • Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines
  • Valproic acid

Pyrantel Pamoate

Mechanism of action

  • Works mainly against luminal organisms
  • Acts as a depolarizing neuromuscular blocking agent → paralyzes helminths → expulsion:
    • Causes acetylcholine release
    • Inhibits cholinesterase

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption: poor oral absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption 
  • Excretion: feces

Indications

Pyrantel pamoate is used for intestinal nematodes, including:

  • Ascaris Ascaris Ascaris is a genus of parasitic nematodes. The infection, ascariasis, is most often caused by A. lumbricoides. Transmission occurs primarily via ingestion of water or food contaminated with Ascaris eggs. Most patients with ascariasis are asymptomatic. Ascaris/Ascariasis lumbricoides 
  • Ancylostoma duodenale
  • Enterobius Enterobius Enterobiasis is a helminth infection caused by Enterobius vermicularis, also known as a pinworm. This infection is typically seen in children and is transmitted through the fecal-oral route. The primary clinical feature is anal pruritus, but patients are often asymptomatic. Enterobius/Enterobiasis vermicularis 
  • Necator americanus
  • Trichostrongylus spp.

Adverse effects

  • Abdominal cramps
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Nausea and vomiting 
  • Headache
  • Dizziness

Contraindications

  • Severe liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease (use with caution)
  • Known hypersensitivity

Praziquantel

Mechanism of action

  • ↑ Cell permeability to calcium → uncontrolled calcium influx → muscle contraction and paralysis 
  • Tegument vacuolization and disintegration

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption: well absorbed
  • Distribution:
    • Protein-bound
    • Crosses blood–brain barrier
  • Metabolism:
    • Extensive 1st-pass metabolism 
    • Hepatic
  • Excretion: urine (approximately 99% as metabolites)

Indications

Praziquantel is used for many trematode and cestode infections:

  • Trematodes:
    • Schistosoma Schistosoma Schistosomiasis is an infection caused by Schistosoma, a trematode. Schistosomiasis occurs in developing countries with poor sanitation. Freshwater snails are the intermediate host and are transmitted to humans through skin contact with contaminated fresh water. The clinical presentation occurs as a result of the host's immune response to antigens from the eggs. Schistosoma/Schistosomiasis spp.
    • Clonorchis sinensis 
    • Opisthorchis viverrini
  • Cestodes:
    • Taenia Taenia Taenia belong to the Cestoda class of helminths. Humans are infected with these tapeworms by eating undercooked beef (T. saginata) or pork (T. solium and T. asiatica). Taeniasis is often asymptomatic, but the ingestion of larvae can cause abdominal discomfort, nausea, and constipation or diarrhea. Taenia/Taeniasis spp.
    • Diphyllobothrium Diphyllobothrium Diphyllobothriasis represents an intestinal parasitic infection caused by the cestode Diphyllobothrium. Diphyllobothriasis is acquired by ingestion of late larvae in undercooked or raw fish. The clinical presentation of diphyllobothriasis varies from asymptomatic, nonspecific symptoms to intestinal obstruction, and/or vitamin B12 deficiency. Diphyllobothrium/Diphyllobothriasis latum
    • Echinococcus Echinococcus Echinococcosis is a parasitic disease caused by Echinococcus tapeworms. Infection most often occurs from the ingestion of Echinococcus eggs in food or water contaminated with dog feces. Signs and symptoms are caused by hydatid cyst development in visceral organs and depend on the species. Echinococcus/Echinococcosis spp.

Adverse effects

  • Dizziness 
  • Headache
  • Drowsiness 
  • Urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives) 
  • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Nausea
  • Fever 
  • Cardiac arrhythmias
  • Mild ↑ liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
  • Exacerbation of neurologic abnormalities (in patients with CNS infection, such as neurocysticercosis)

Contraindications

  • Known hypersensitivity
  • Ocular cysticercosis (parasite destruction may cause irreparable eye damage)
  • Use with caution with:
    • Severe liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease
    • Atrioventricular block Atrioventricular block Atrioventricular (AV) block is a bradyarrhythmia caused by delay, or interruption, in the electrical conduction between the atria and the ventricles. Atrioventricular block occurs due to either anatomic or functional impairment, and is classified into 3 types. Atrioventricular Block
    • Arrhythmias

References

  1. Holden-Dye L, Walker RJ. (2007). Antihelminthic drugs. WormBook 2:1–13. https://pubmed.ncbi.nlm.nih.gov/17988075/
  2. Liu LX, Weller PF. (1996). Antiparasitic drugs. NEJM. 334(18), 1178-84. https://pubmed.ncbi.nlm.nih.gov/8602186/
  3. Weller PF. (2021). Anthelminthic therapies. UpToDate. Retrieved August 5, 2021, from https://www.uptodate.com/contents/anthelminthic-therapies
  4. UptoDate Lexicomp. Retrieved September 4, 2021, from:
  5. Campbell S, Soman-Faulkner K. (2020). Antiparasitic drugs. StatPearls. Retrieved September 4, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK544251/
  6. Rosenthal PJ. (2012). Clinical pharmacology of the antihelminthic drugs. In: Katzung BG, Masters SB, Trevor AJ (Eds.), Basic & Clinical Pharmacology. 12th ed. McGraw-Hill, pp. 937–947). https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf

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