Anthelmintic Action

The BZAs inhibit microtubule polymerization by binding to ß-tubulin. The selective toxicity of these agents likely results because the BZAs bind parasite ß-tubulin with much higher affinity than they do the mammalian protein. Drug resistance in nematodes may involve expression of a mutated ß-tubulin. There is no evidence of emerging resistance among human nematodes.

The BZAs are versatile anthelmintic agents, particularly against GI nematodes, where their action is not dictated by systemic drug concentration. Mebendazole and albendazole are highly effective in treating the major STH infections (ascariasis, enterobiasis, trichuriasis, and hookworm) as well as less common human nematode infections. These drugs are active against both larval and adult stages of nematodes, and they are ovicidal for Ascaris and Trichuris. Immobilization and death of susceptible GI parasites occur slowly, and their clearance from the GI tract may not be complete until several days after treatment.

Albendazole is more effective than mebendazole against strongyloidiasis, cystic hydatid disease caused by E. granulosus, and neurocysticercosis caused by larval forms of T. solium. The BZAs probably are active against the intestinal stages of T. spiralis, but likely do not affect the larval stages in tissues. Albendazole is highly effective against the migrating forms of dog and cat hookworms that cause cutaneous larval migrans. Regimens in which albendazole with either ivermectin or diethylcarbamazine are given as single annual doses show great promise for the elimination of LF. Certain microsporidia that cause intestinal infections in human immunodeficiency virus (HlV)-infected individuals respond partially (Enterocytozoon bieneusi) or completely (Enterocytozoon intestinalis and related species) to albendazole.

ABSORPTION, FATE, AND EXCRETION Thiabendazole is absorbed rapidly after oral ingestion and reaches peak plasma concentrations after 1 hour. Most of the drug is excreted in the urine within 24 hours as 5-hydroxythiabendazole, conjugated either as the glucuronide or the sulfate. Tablet formulations of mebendazole are poorly and erratically absorbed, and plasma concentrations are low. The low systemic bioavailability (22%) of mebendazole results from a combination of poor absorption and rapid first-pass hepatic metabolism. Mebendazole is ~95% bound to plasma proteins and is extensively metabolized. The major metabolites have lower rates of clearance than does mebendazole and apparently are inactive. Conjugates of mebendazole and its metabolites have been found in bile, but little unchanged mebendazole appears in the urine.

Albendazole is variably absorbed after oral administration. A fatty meal enhances absorption. After a 400-mg oral dose, albendazole cannot be detected in plasma, because the drug is rapidly metabolized in the liver to its sulfoxide, which has potent anthelmintic activity. Both the (+) and (—) enantiomers of albendazole sulfoxide are formed; the (+) enantiomer reaches much higher peak plasma concentrations and is cleared much more slowly. Albendazole sulfoxide is ~70% bound to plasma proteins and has a variable plasma t/2 (~4-15 hours). It is well distributed into various tissues including hydatid cysts, probably explaining its greater efficacy for tissue-dwelling helminths. Formation of albendazole sulfoxide is catalyzed by both microsomal flavin monooxy-genase and CYP isoforms in the liver. Albendazole metabolites are excreted mainly in the urine.

THERAPEUTIC USES Thiabendazole (mintezol) generally has been replaced by newer agents. Mebendazole is highly effective against GI nematodes and is particularly valuable for mixed infections. Mebendazole always is taken orally, and the same dosage schedule applies to adults and children >2 years of age. For treatment of enterobiasis, a single 100-mg tablet is taken, repeated after 2 weeks. For control of ascariasis, trichuriasis, or hookworm infections, the recommended regimen is 100 mg of mebendazole taken in the morning and evening for 3 consecutive days (or a single 500-mg tablet administered once). If the patient is not cured 3 weeks after treatment, a second course should be given. The 3-day mebendazole regimen is more effective than single doses of either mebendazole (500 mg) or albendazole (400 mg).

Like mebendazole, albendazole provides safe and effective therapy against infections with GI nematodes, including mixed infections of Ascaris, Trichuris, and hookworms. For treatment of enterobiasis, ascariasis, trichuriasis, and hookworm, albendazole is taken as a single oral 400-mg dose by adults and children >2 years of age. In children between the ages of 12 and 24 months, the WHO recommends a reduced dose of 200 mg. Cure rates for light-to-moderate Ascaris infections typically are >97%, although heavy infections may require therapy for 2-3 days. A 400-mg dose of albendazole appears to be superior to a 500-mg dose of mebendazole for curing hookworm infections.

Albendazole is the drug of choice for cystic hydatid disease due to E. granulosus. While the drug provides only a modest cure rate when used alone, it produces superior results when used in conjunction with either surgery to remove cysts or aspiration/injection of cysts with protoscolicidal agents. A typical dosage regimen for adults is 400 mg given twice a day (for children 15 mg/kg/day with a maximum of 800 mg) for 1-6 months. While the best drug available, albendazole is only marginally effective for alveolar echinococcosis caused by E. multilocularis, and surgical intervention often is needed.

Albendazole also is the preferred treatment of neurocysticercosis caused by larval forms of T. solium. The recommended dose is 400 mg given twice a day for adults for 8-30 days, depending on the number, type, and location of the cysts. For children, the dose is 15 mg/kg/day (maximum 800 mg) in two doses for 8-30 days. The course can be repeated as necessary, as long as liver and bone marrow toxicities are monitored. To reduce inflammatory side effects, glucocorticoids are usually given for several days before initiating albendazole therapy. Such pretreatment also increases plasma levels of albendazole sulfoxide. Therapy with either albendazole or praziquantel should include consideration of anticonvulsant therapy, the possible development of complications of arachnoiditis, vasculitis, or cerebral edema, and the need for surgical intervention should obstructive hydrocephalus occur. Albendazole, 400 mg/day, also has shown efficacy for therapy of microsporidial intestinal infections in patients with AIDS.

Albendazole is combined with either diethylcarbamazine or ivermectin in programs directed toward controlling LF. By annual dosing with combination therapy for 4-6 years, the goal is to maintain the microfilaremia at such low levels that transmission cannot occur for a period that corresponds to the duration of fecundity of adult worms. Albendazole is given with diethylcarbamazine to control LF in most parts of the world. To avoid serious reactions to dying microfilariae, an albendazole/ivermectin combination is recommended in locations where filariasis coexists with either onchocerciasis or loiasis.

TOXICITY, SIDE EFFECTS, PRECAUTIONS, AND CONTRAINDICATIONS The

BZAs generally have excellent safety profiles. Side effects, primarily mild GI symptoms, occur in ~1% of treated children.

The clinical utility of thiabendazole in adults is compromised by its toxicity, which has diminished its clinical use. Frequent side effects include GI upset, fatigue, drowsiness, and headache. Occasional fever, rash, erythema multiforme, hallucinations, and sensory disturbances have been reported. Angioedema, shock, tinnitus, convulsions, and intrahepatic cholestasis, and crystalluria are rare complications. Transient leukopenia has been noted. Thiabendazole is hepatotoxic and should be used with caution in patients with hepatic disease. The effects of thiabendazole in pregnant women have not been studied adequately, so it should be used in pregnancy only when the potential benefit justifies the risk.

Mebendazole does not routinely cause significant systemic toxicity, even in the presence of anemia and malnutrition. Transient symptoms of abdominal pain, distention, and diarrhea have occurred with massive infestation and expulsion of GI worms. Rare side effects in patients treated with high doses of mebendazole include allergic reactions, alopecia, reversible neutropenia, agranulocytosis, and oligospermia. Reversible elevation of serum transaminases may occur. Mebendazole may be associated with occipital seizures. It should not be used in patients who have experienced allergic reactions to the agent.

Albendazole also produces few side effects when used for short-term therapy of GI helminthiasis, even in patients with heavy worm burdens. Transient mild GI symptoms (epigastric pain, diarrhea, nausea, and vomiting) occur in ~1% of treated individuals. Dizziness and headache occur on occasion. In school-age mass treatments, the incidence of side effects with albendazole is very low. Allergic phenomena rarely occur and usually resolve after 48 hours.

Even in long-term therapy of cystic hydatid disease and neurocysticercosis, albendazole is well tolerated by most patients. The most common side effect is an increase in serum aminotrans-ferases, which return to normal upon drug cessation; rarely jaundice or cholestasis may occur. Liver function tests should be monitored during protracted albendazole therapy, and the drug is not recommended for patients with cirrhosis. Especially if not pretreated with glucocorticoids, some patients with neurocysticercosis may experience serious neurological sequelae. Other side effects during extended therapy include GI pain, severe headaches, fever, fatigue, alopecia, leukopenia, and thrombocytopenia.

The BZAs display remarkably few interactions with other drugs. The most versatile member of this family, albendazole, probably induces its own metabolism, and plasma levels of its sulfoxide metabolites can be increased by coadministration of glucocorticoids and possibly praziquantel. Caution is advised when using high doses of albendazole together with general inhibitors of hepatic CYPs.

Use in Pregnancy Both albendazole and mebendazole are embryotoxic and teratogenic in rats. In postmarketing surveys of women who inadvertently consumed mebendazole during the first trimester, the incidence of spontaneous abortion and malformations did not exceed that of the general population; comparable studies with albendazole are not available. A review of the risk of congenital abnormalities from BZAs concluded that their use during pregnancy is not associated with an increased risk of major congenital defects; nonetheless, it is recommended that treatment should be avoided during the first trimester of pregnancy.

Use in Young Children The WHO concluded that the BZAs may be used to treat children past the first year who are at risk for adverse consequences caused by STHs; a reduced dose of albendazole (200 mg) is used in children between the ages of 12-24 months.

DIETHYLCARBAMAZINE Diethylcarbamazine is a first-line agent for control and treatment of lymphatic filariasis and for therapy of tropical pulmonary eosinophilia caused by W. bancrofti and Brugia malayi. Although partially effective against onchocerciasis and loiasis, it can cause serious reactions to affected microfilariae. For this reason, ivermectin has replaced diethylcarbamazine for onchocerciasis. Despite its toxicity, diethylcarbamazine remains the best drug available to treat loiasis.

Annual single doses of both diethylcarbamazine and albendazole show considerable promise for the control of lymphatic filariasis in regions where onchocerciasis and loiasis are not endemic.

Diethylcarbamazine (hetrazan) is formulated as the water-soluble citrate salt.

101 Power Tips For Preventing and Treating Headaches

101 Power Tips For Preventing and Treating Headaches

Are you fed up with your frequent headache pain? 101 Simple Ways to Attack Your Headache BEFORE the Pain Starts Guaranteed No Pain, No Fear, Full Control Normal Life Again Headaches can stop you from doing all the things you love. Seeing friends, playing with the kids... even trying to watch your favorite television shows.

Get My Free Ebook


Responses

  • sigismond
    Does anthelminthic reduce blood pressure?
    2 years ago

Post a comment