Clinical pharmacology

Pharmacology of anthelmintics: Table I. Common helminth infections and their alben daz ole, meben daz ole and complications praziquantel Major Disease Complications pathogens Parasitic helminthic infections are an important cause of morbidity and mortality worldwide. The helminths include soil-transmitted Intestinal nematodes (roundworms) intestinal nematodes (roundworms), trematodes (flukes) and Ascaris Ascariasis Lactose intolerance, cestodes (tapeworms) (Table I). lumbricoides (common round- vitamin A malab- worm infection) sorption, intesti- The disease burden caused by worm infestation is unevenly nal obstruction, distributed, with low-income countries being the worst affected. The hepatopancreatic most heavily infested persons are at the highest risk of morbidity disease and are the major source of environmental contamination and Growth and mental further transmission. In low-income countries, soil-transmitted retardation helminths are one of the most important causes of growth and mental retardation, and neurocysticercosis is the main cause of Trichuris Trichuriasis Colitis, Trichuris adult-onset epilepsy (other than trauma). In pregnancy, severe iron trichiura (whipworm dysentery deficiency anaemia due to hookworm infestation can result in poor infection) syndrome, anaemia, maternal, fetal and neonatal outcomes. rectal prolapse Necator Hookworm Intestinal blood Albendazole, mebendazole and praziquantel are the only available americanus or infection loss, iron deficiency anthelmintics in our essential medicines list. These drugs have Ancylostoma anaemia, protein broad-spectrum coverage with high cure rates. However, re- duodenale malnutrition infection is very common. Specific population groups (preschool and school-age children, adolescent girls and pregnant women) Enterobius Enterobiasis Perianal/perineal have been targeted for mass treatment campaigns to reduce vermicularis (pinworm itch with subse- transmission rates. The school-based national control programmes infection) quent scratching have been shown to decrease transmission and to improve growth and excoriation, and cognitive performance in children. Intervention studies in and bacterial pregnant women have also shown that antenatal anthelmintics superinfection in the second trimester led to a substantial increase in maternal Toxocara Toxocariasis: Hepatitis and haemoglobin and an improvement in neonatal outcomes. However, canis (dog) or visceral larva pneumonitis, me- there have been concerns regarding the sustainability of periodic Toxocara cati migrans (usually ningoencephalitis, de-worming and the emergence of resistance. (cat) liver and lungs, cerebritis, seizures, This review briefly discusses the common helminth infections and rarely brain) blindness focuses on the pharmacology of the few drugs available to treat and ocular larva them (albendazole, mebendazole and praziquantel). migrans Trematodes (flukes) Common helminth infections Schistosoma Intestinal and uri- Pulmonary and mansoni and nary (bilharzia) portal hyperten- Roundworms Schistosoma schistosomiasis sion, haematu- Soil-transmitted helminths are a group that cause human infection haematobium ria, obstructive through skin contact with eggs or larvae that thrive in warm and uropathy, bladder moist soil in tropical or subtropical areas. Migration of the larval cancer, spinal cord forms of some helminths may cause cutaneous larva migrans or granulomas systemic features, usually including pulmonary involvement, with Cestodes (tapeworms) eosinophilia (known as visceral larva migrans). Surgical complica- tions may occur owing to intestinal obstruction (Table I). Mixed Taenia Taeniasis or Appendicitis, infection with intestinal worms (Ascaris lumbricoides, Trichuris saginata cysticercosis cholangitis trichiura and Necator americanus or Ancylostoma duodenale) is (beef) and Acquired adult- very common, with evidence of household aggregation of infec- Taenia solium onset epilepsy tion. (pork) Enterobiasis is caused by the human pinworm Enterobius Echinococcus Hydatid disease Hepatic, pulmonary vermicularis. Humans are the only host. Enterobiasis seldom granulosus or spinal brain causes serious clinical disease. Eggs are deposited on perianal folds. hydatid cycts Self-infection occurs by transferring infective eggs to the mouth with hands that have scratched the perianal area. After ingestion nocturnally outside the anus and deposit eggs while crawling on of infective eggs, the larvae hatch in the small intestine and the the skin of the perianal area. Person-to-person transmission can adults establish themselves in the colon. Gravid females migrate also occur through handling of contaminated clothes or bedlinen.

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Enterobiasis may also be acquired through a common presentation but patients may form cysts of varying sizes (usually 1 - 15 cm surfaces that are contaminated with pinworm present with hepatosplenic schistosomiasis in diameter). Slow-growing solitary cysts are eggs (e.g. curtains, carpets). A small number without prior intestinal symptoms (Table I). common, but multiple cysts can occur. The of eggs may become airborne and be inhaled. liver and lungs are predominantly affected, These would be swallowed and follow the Tapeworms but any system can be involved including the same development as ingested eggs. Retro- central nervous system and musculoskeletal Taeniasis is spread by ingestion of raw or infection (migration of larvae from the anus system. Morbidity depends on the number, undercooked beef (Taenia saginata) or pork back to the rectum) may also occur. size, and developmental status of the cyst, (T. solium) infected with cysticerci. Humans the involved organ, the localisation of the Toxocariasis results from zoonotic are the definitive hosts. After ingestion of cyst within the organ, pressure effects of transmission of the roundworms Toxocara infected beef or pork in the intestine the the cyst and the host defence mechanism. canis and T. cati from dogs and cats, cysticercus develops over 2 months into an The definitive treatment is by percutaneous respectively. Humans are the accidental hosts adult tapeworm, which can survive for years. aspiration and injection of scolicidal agents, and infection is caused by ingestion of eggs Intestinal taeniasis is usually asymptomatic followed by re-aspiration. This has largely containing larvae shed in dog and cat faeces or produces mild abdominal symptoms. replaced surgery, which carries the risk by hand to mouth contact. After ingestion Patients may also report the passage of of perioperative morbidity, recurrence of the eggs release larvae that penetrate the proglottids in the stool. cysts, and spillage of hydatid fluid from stomach and migrate through the liver, Humans may act as intermediate hosts for the cysts, which can lead to anaphylaxis lungs and central nervous system, causing T. solium, with the development of tissue and dissemination of infection. Adjunctive mechanical and immunological damage to cysts (cysticercosis). Neurocysticercosis medical therapy is used before aspiration or the tissues (Table I). The host inflammatory is the infestation of the central nervous surgery, or in cases not suitable for either response that follows usually kills the larvae system and its coverings by the larval stage procedure, and is discussed below. or forces them into arrested development. of the pork tapeworm T. solium. It is the most common helminthic infestation of the Treatment of helminthic infections Flukes central nervous system and is a leading cause Anthelmintic drugs have a broad spectrum Schistosoma (trematode) infections are of acquired epilepsy worldwide. Diagnosis of activity. They can be used as a single transmitted after direct contact with fresh has improved with neuro-imaging. Medical dose for several infections and are generally water harbouring free-swimming larval treatment (albendazole or praziquantel) well tolerated. Briefly discussed below forms of the parasites. They penetrate intact and occasionally surgical treatment are is the pharmacology of the widely used human skin and enter capillaries and then complementary in carefully selected cases. anthelmintics i.e. albendazole, mebendazole migrate to the portal venous system where and praziquantel (Table II). they mature and unite. Acute schistosomiasis, Hydatid disease is a zoonotic infection also known as Katayama fever, is a form caused by Echinococcus granulosus. Albendazole and mebendazole– of visceral larva migrans. The adult male Domestic dogs are definitive hosts, sheep and female pairs ultimately migrate to the are usually the intermediate hosts and benzimidazole derivatives superior mesenteric veins (S. mansoni) and humans may be accidental intermediate Mebendazole and albendazole are vesical and ureteric veins (S. haematobium). hosts. Human infection occurs when eggs benzimidazole derivatives. The mechanism The eggs are shed in the faeces and urine are accidentally ingested. The larvae invade of action is blocking glucose uptake in and transmission continues. Haematuria is tissues and develop in internal organs to susceptible helminths, thus depleting energy

Table II. Recommended anthelmintic dosing regimen for various indications (adapted from the South African Medicines Formulary, 8th ed., 2008)

Drug Infection Dosing regimen (oral route) Albendazole Roundworm, hookworm and pinworm 200 mg single dose in children 1 - 2 yrs 400 mg single dose in child >2 yrs or adult Whipworm 400 mg daily for 3 days, may repeat after 3 weeks Taeniasis (intestinal) Toxocariasis 5 - 10 mg/kg for 5 days Hydatid disease 400 mg twice daily (or 10 - 15 mg/kg/d) for 3 - 6 months Neurocysticercosis 15 mg/kg/d in 3 divided doses for 14 days Mebendazole Roundworm, pinworm and whipworm 100 mg twice daily for 3 days or 500 mg as a single dose, repeat after 3 - 4 weeks if necessary Pinworm 100 mg single dose, repeated after 2 weeks if necessary Hookworm infection 100 mg twice daily for 3 days Toxocariasis 100 - 200 mg twice daily for 5 days Taeniasis (intestinal) 100 mg twice daily for 6 days Praziquantel Schistosomiasis 40 mg/kg as single dose or in 2 divided doses Intestinal taeniasis 5 - 10 mg/kg as a single dose Cysticercosis 50 mg/kg in 3 divided doses for 14 days

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required for their survival. They are useful reported. When prolonged therapy or is also more effective than praziquantel in in single doses for mixed intestinal worm higher doses of albendazole are used for neurocysticercosis. Mebendazole also has a infections as they have a broad spectrum. For hydatid disease or cysticercosis leucopenia, broad spectrum against intestinal nematodes. example, a recent meta-analysis by Keiser abnormalities in liver functions, allergic Both have lower efficacy against trichuriasis. showed that single doses of albendazole and reactions and alopecia have been reported. Praziquantel is the drug of choice for mebendazole have high cure rates (88 - 95%) Regular monitoring of the alanine schistosomiasis and is also effective against for ascariasis. For hookworm infections, transaminase and white cell count should be intestinal taeniasis and neurocysticercosis. albendazole was more efficacious than done. Despite the high cure rates re-infection mebendazole; hence a longer course of the is very high and preventive measures are latter is recommended (Table II). Cure rates Praziquantel – pyrazinoisoquinoline necessary. These include: improving basic for trichuriasis with single-dose regimens derivative sanitation, proper hygiene education, are low – 28% (95% CI 13 - 39%) and 36% Praziquantel is a pyrazinoisoquinoline wearing shoes, treatment of all household (95% CI 16 - 51%) for albendazole and derivative whose mechanism of action is members, periodic mass treatment of mebendazole, respectively. the increase in muscular activity, causing targeted population groups and de-worming Albendazole has a wider spectrum than contraction and spastic paralysis of the of livestock and domestic animals. mebendazole, being effective against parasite. It also causes tegumental damage strongyloidiasis, toxocariasis, hydatid of the susceptible parasite. Further reading disease, and cysticercosis. Of note, when It is the agent of choice for schistosomiasis Benthony J, Brooker S, Albonico M, et al. Soil- transmitted helminth infections: ascariasis, albendazole is used for neurocysticercosis and can be used as a single dose, with high or ocular cysticercosis, concomitant steroid trichuriasis, and hookworm. Lancet 2006; 367: cure rates and substantial reduction of the 1521-1532. therapy with strict supervision may be worm burden and egg production. It is also indicated to reduce the host inflammatory Del Brutto OH, Roos KL, Coffey CS, Garcia useful for intestinal tapeworm infections HH. Meta-analysis: Cysticidal drugs for response to the death of the parasite. The (taeniasis). Praziquantel has been used neurocysticercosis: albendazole and praziquantel. use of anthelmintic drugs for therapy for neurocysticercosis, but the duration of Ann Intern Med 2006; 145: 43-51. of neurocysticercosis results in better therapy is longer than with albendazole, Dickson R, Awasthi S, Williamson P, Demellweek, resolution of viable parenchymal cysts and which most experts now prefer. Garner P. Effects of treatment for intestinal helminth lower risk of recurrence, and reduces seizure infection on growth and cognitive perfomance in frequency when compared with placebo. Praziquantel can be safely used in children children: systemic review of randomised trials. BMJ In hydatid disease, albendazole reduces older than 2 years. Risk-benefit analysis of 2000; 320: 1697-1701. the viability of protoscolices and cysts. its use for schistosomiasis in pregnancy Gibbon CJ, Blockman M, eds. South African suggests that treatment should be offered Medicines Formulary, 8th ed. Cape Town: Health Its active metabolite is active against the and Medical Publishing Group of the South African larval cestodes. Drug therapy is indicated in on an individual basis and pregnant women Medical Association, 2008. should be included in mass treatment inoperable cases (where long-term therapy Hotez PJ, Wilkins P. Toxocariasis: American’s is used), spontaneous or operative rupture campaigns. most common neglected infection of poverty and a of the cyst, or before and after aspiration The adverse effects are usually mild helminthiasis of global importance? PLoS Negl Trop Dis 2009; 3: doi: 10.1371/journal.pntd.0000400. and surgery. and transient. However, when used in neurocysticercosis inflammatory response Keiser J, Utzinger J. Efficacy of current drugs There are limited data in children under against soil-transmitted helminth infections: 1 year of age. In children older than to dead and dying parasites may lead to systemic review and meta-analysis. JAMA 2008; a year, treatment with single doses fever, cerebral oedema, raised intracranial 299: 1937-1948 showed improvement in physical and pressure and convulsion. Sinha S, Sharma BS. Neurocysticercosis: A review intellectual growth. Animal studies showed of current status and management. J Clin Neurosci teratogenicity; these drugs are therefore Conclusion 2009; 16: 867-876. contraindicated in the first trimester. To summarise, albendazole, the newer Phumla Sinxadi, MB ChB, DA (SA) However, the benefits almost certainly benzimidazole derivative, is effective against Gary Maartens, MB ChB, MMed, FCP (SA), outweigh the risks when treatment is given most intestinal nematode and cestode DTM&H after the first trimester. infections and is, therefore, the drug of choice Division of Clinical Pharmacology in mixed worm infection. When prescribed Department of Medicine Both albendazole and mebendazole University of Cape Town are generally well tolerated in doses as a single dose for treating hookworm infection, it is better than mebendazole. Corresponding author: Phumla Sinxadi (phumla. recommended for intestinal worms. [email protected]) Gastrointestinal discomfort has been It is a useful adjunct in hydatid disease. It

In a nutshell • Albendazole and mebendazole are broad-spectum anthelmintics effective against soil-transmitted helminths. • Albendazole has an extended spectrum against tapeworm infection and is therefore the drug of choice in mixed infestation. • Praziquantel is the drug of choice for schistomiasis. • Praziquantel or albendazole results in better resolution of viable parenchymal cysts and less recurrence of cysts, and reduced frequency of seizures in neurocysticercosis. • Mass treatment campaigns with single doses of albendazole or mebendazole or praziquantel are important tools for reducing the disease burden caused by helminths. • Preventive measures reduce transmission and must be emphasised.

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