Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 53. Antihelminthic Drugs

Antihelminthic Drugs: Introduction

Antihelminthic drugs have diverse chemical structures, mechanisms of action, and properties. Most were discovered by empiric screening methods; many act against specific parasites, and few are devoid of significant toxicity to host cells. In addition to the direct toxicity of the drugs, reactions to dead and dying parasites may cause serious toxicity in patients. In the text that follows, the drugs are divided into 3 groups on the basis of the type of helminth primarily affected (nematodes, trematodes, and cestodes). The drugs of choice and alternative agents for selected important helminthic infections are listed in Table 53-1.

TABLE 53-1 Drugs for the treatment of helmintic infections.

Infecting Organism Drugs of Choice Alternative Drugs Nematodes Ascaris lumbricoides (roundworm) Albendazole or mebendazole or pyrantel pamoate Piperazine Necator americanus & Ancylostoma duodenale (hookworm) Pyrantel pamoate or albendazole or mebendazole Trichuris trichiura (whipworm) Albendazole or mebendazole Pyrantel pamoate Strongyloides stercoralis (threadworm) Ivermectin Albendazole, mebendazole Enterobius vermicularis (pinworm) Mebendazole or pyrantel pamoate Albendazole Trichinella spiralis (trichinosis) Mebendazole (+/- corticosteroids) Albendazole Cutaneous larva migrans Albendazole or ivermectin Wuchereria bancrofti and Brugia malayi (filariasis) Diethylcarbamazine Ivermectin Onchocerca volvulus (onchocerciasis) Ivermectin Trematodes (flukes) Schistosoma haematobium Praziquantel Metrifonate Schistosoma mansoni Praziquantel Oxamniquine Schistosoma japonicum Praziquantel Paragonimus westermani Praziquantel Fasciola hepatica (sheep liver fluke) Bithional or triclabendazole Fasciolopsis buski (large intestinal fluke) Praziquantel or niclosamide Cestodes (tapeworms) Taenia saginata (beef tapeworm) Praziquantel or niclosamide Mebendazole Taenia solium (pork tapeworm) Praziquantel or niclosamide Cysticercosis (pork tapeworm larval stage) Albendazole Praziquantel Diphylobothrium latum (fish tapeworm) Praziquantel or niclosamide Echinococcus granulosus (hydatid disease) Albendazole

Drugs That Act Against Nematodes

The medically important intestinal nematodes responsive to drug therapy include Enterobius vermicularis (pinworm), Trichuris trichiuria (whipworm), Ascaris lumbricoides (roundworm), Ancyclostoma and Necator species (hookworms), and Strongyloides stercoralis (threadworm). More than 1 billion persons worldwide are estimated to be infected by intestinal nematodes. Pinworm infections are common throughout the United States, and hookworm and threadworm are endemic in the southern United States. Tissue nematodes responsive to drug therapy include Ancyclostoma species, which cause cutaneous larva migrans. Species of Dracunculus, Onchocerca, Toxocara, and Wuchereria bancrofti (the cause of filariasis) all are responsive to drug treatment. The number of persons worldwide estimated to be infected by tissue nematodes exceeds 0.5 billion.

Albendazole

Mechanisms

The action of albendazole is thought to involve inhibition of microtubule assembly. The drug is larvicidal in ascariasis, cystercercosis, hookworm, and hydatid disease and is ovicidal in ascariasis, ancyclostomiasis, and trichuriasis.

Clinical Use

Albendazole has a wide antihelminthic spectrum. It is a primary drug for ascariasis, hookworm, pinworm, and whipworm infections and an alternative drug for treatment of threadworm infections, filariasis, and both visceral and cutaneous larva migrans. Albendazole is also used in hydatid disease and is active against the pork tapeworm in the larval stage (cysticercosis).

Toxicity

Albendazole has few toxic effects during short courses of therapy (1-3 d). However, a reversible leukopenia, alopecia, and elevation of liver function enzymes can occur with more prolonged use. Long-term animal toxicity studies have described bone marrow suppression and fetal toxicity. The safety of the drug in pregnancy and young children has not been established.

Diethylcarbamazine

Mechanisms

Diethylcarbamazine immobilizes microfilariae by an unknown mechanism, increasing their susceptibility to host defense mechanisms.

Clinical Use

Diethylcarbamazine is the drug of choice for several filarial infections including those caused by Wucheria bancrofti and Brugia malayi and for eye worm disease (loa loa). The drug undergoes renal elimination, and its half-life is increased significantly by urinary alkalinization.

Toxicity

Adverse effects include headache, malaise, weakness, and anorexia. Reactions to proteins released by dying filariae include fever, rashes, ocular damage, joint and muscle pain, and lymphangitis. In onchocerciasis, the reactions are more intense and include most of the symptoms described as well as hypotension, pyrexia, respiratory distress, and prostration.

Ivermectin

Mechanisms

Ivermectin intensifies -aminobutyric acid (GABA)-mediated neurotransmission in nematodes and causes immobilization of parasites, facilitating their removal by the reticuloendothelial system. Selective toxicity results because in humans GABA is a neurotransmitter only in the CNS, and ivermectin does not cross the blood-brain barrier.

Clinical Use

Ivermectin is the drug of choice for onchocerciasis, cutaneous larva migrans, strongyloidiasis, and some forms of filariasis.

Toxicity

Single-dose oral treatment in onchocerciasis results in reactions to the dying worms, including fever, headache, dizziness, rashes, pruritus, tachycardia, hypotension, and pain in joints, muscles, and lymph glands. These symptoms are usually of short duration, and most can be controlled with antihistamines and nonsteroidal anti-inflammatory drugs. Avoid other drugs that enhance GABA activity. Ivermectin should not be used in pregnancy.

Mebendazole

Mechanism

Mebendazole acts by selectively inhibiting microtubule synthesis and glucose uptake in nematodes.

Clinical Use

Mebendazole is a primary drug for treatment of ascariasis and for pinworm and whipworm infections. Mebendazole has also been used as a backup drug in visceral larval migrans. Less than 10% of the drug is absorbed systemically after oral use, and this portion is metabolized rapidly by hepatic enzymes. Plasma levels may be decreased by carbamazepine or phenytoin and increased by cimetidine.

Toxicity

Mebendazole toxicity is usually limited to gastrointestinal irritation, but at high doses agranulocytopenia and alopecia have occurred. The drug is teratogenic in animals and therefore contraindicated in pregnancy.

Piperazine

Mechanism

Piperazine paralyzes ascaris by acting as an agonist at GABA receptors. The paralyzed roundworms are expelled live by normal peristalsis.

Clinical Use

Piperazine is an alternative drug for ascariasis.

Toxicity

Mild gastrointestinal irritation is the most common side effect. Piperazine should not be used in pregnant patients or those with hepatic or renal dysfunction or seizure disorders.

Pyrantel Pamoate

Mechanism

Pyrantel pamoate stimulates nicotinic receptors present at neuromuscular junctions of nematodes. Contraction of muscles occurs, followed by a depolarization-induced paralysis.The drug has no actions on flukes or tapeworms.

Clinical Use

Pyrantel pamoate has wide activity against nematodes killing adult worms in the colon but not the eggs. It is a drug of choice for hookworm and roundworm infections and an alternative drug for pinworms. The drug is poorly absorbed when given orally.

Toxicity

Adverse effects are minor but include gastrointestinal distress, headache, and weakness. Use with caution in patients with hepatic dysfunction.

Thiabendazole

Mechanism

Thiabendazole is a structural congener of mebendazole and has a similar action on microtubules.

Clinical Use

Because of its adverse effects, thiabendazole is an alternative drug in strongyloidiasis and trichinosis (adult worms). Thiabendazole is rapidly absorbed from the gut and is metabolized by liver enzymes. The drug has anti-inflammatory and immunorestorative actions in the host.

Toxicity

Thiabendazole is much more toxic than other benzimidazoles or ivermectin, so these other drugs are preferred. Its toxic effects include gastrointestinal irritation, headache, dizziness, drowsiness, leukopenia, hematuria, and allergic reactions, including intrahepatic cholestasis. Reactions caused by dying parasites include fever, chills, lymphadenopathy, and skin rash. Irreversible liver failure and fatal Stevens-Johnson syndrome have also been reported. Avoid in pregnant patients or those with hepatic or renal disease.

Skill Keeper: Antimicrobial Chemotherapy in Pregnancy

Mebendazole is widely used for the treatment of nematode infections but is contraindicated in the pregnant patient because of possible embryotoxicity. Think back over the drugs used for the treatment of bacterial, fungal, protozoal, and viral infections.

1. Which drugs are associated with a greater risk compared with benefit in pregnancy?

2. Which drugs are nominally contraindicated in pregnancy but might be used if the benefit were judged to outweigh the risk?

The Skill Keeper Answers appear at the end of the chapter.

Drugs That Act Against Trematodes

The medically important trematodes include Schistosoma species (blood flukes, estimated to affect more than 150 million persons worldwide), Clonorchis sinensis (liver fluke, endemic in Southeast Asia), and Paragonimus westermani (lung fluke, endemic to both Asia and the Indian subcontinent). With few exceptions, fluke infections respond well to praziquantel.

Praziquantel

Mechanism

Praziquantel increases membrane permeability to calcium, causing marked contraction initially and then paralysis of trematode and cestode muscles; this is followed by vacuolization and parasite death.

Clinical Use

Praziquantel has a wide antihelminthic spectrum that includes activity in both trematode and cestode infections. It is the drug of choice in schistosomiasis (all species), clonorchiasis, and paragonimiasis and for infections caused by small and large intestinal flukes. The drug is active against immature and adult schistosomal forms. Praziquantel is also 1 of 2 drugs of choice (with niclosamide) for infections caused by cestodes (all common tapeworms) and an alternative agent (to albendazole) in the treatment of cysticercosis.

Pharmacokinetics

Absorption from the gut is rapid, and the drug is metabolized by the liver to inactive products.

Toxicity

Common adverse effects include headache, dizziness and drowsiness, malaise, and, less frequently, gastrointestinal irritation, skin rash, and fever. Neurologic effects can occur in the treatment of neurocyticercosis including intracranial hypertension and seizures. Corticosteroid therapy reduces the risk of the more serious reactions. Praziquantel is contraindicated in ocular cysticercosis. In animal studies, the drug increased abortion rate.

Bithionol

Clinical Use

Bithionol is a codrug of choice (with triclabendazole) for treatment of fascioliasis (sheep liver fluke) and an alternative agent in paragonimiasis. The mechanism of action of the drug is unknown. Bithionol is orally effective and is eliminated in the urine.

Toxicity

Common adverse effects of bithionol include nausea and vomiting, diarrhea and abdominal cramps, dizziness, headache, skin rash (possibly a reaction to dying worms), and phototoxicity. Less frequently, pyrexia, tinnitus, proteinuria, and leukopenia may occur.

Metrifonate

Metrifonate is an organophosphate prodrug that is converted in the body to the cholinesterase inhibitor dichlorvos. The active metabolite acts solely against Schistosoma haematobium (the cause of bilharziasis). Toxic effects occur from excess cholinergic stimulation. The drug is contraindicated in pregnancy.

Oxamniquine

Oxamniquine is effective solely in Schistosoma mansoni infections (intestinal bilharziasis), acting on male immature forms and adult schistosomal forms. The drug causes paralysis of the worms, but its precise mechanism is unknown. Dizziness is a common adverse effect (no driving for 24 h); headache, gastrointestinal irritation, and pruritus may also occur. Reactions to dying parasites include eosinophilia, urticaria, and pulmonary infiltrates. It is not advisable to use the drug in pregnancy or in patients with a history of seizure disorders.

Drugs That Act Against Cestodes (Tapeworms)

The 4 medically important cestodes are Taenia saginata (beef tapeworm), Taenia solium (pork tapeworm, which can cause cysticerci in the brain and the eyes), Diphyllobothrium latum (fish tapeworm), and Echinococcus granulosus (dog tapeworm, which can cause hydatid cysts in the liver, lungs, and brain). The primary drugs for treatment of cestode infections are praziquantel (see prior discussion) and niclosamide.

Niclosamide

Mechanism

Niclosamide may act by uncoupling oxidative phosphorylation or by activating ATPases.

Clinical Use

Niclosamide is an alternative drug to praziquantel for infections caused by beef, pork, and fish tapeworm. It is not effective in cysticercosis (for which albendazole or praziquantel is used) or hydatid disease caused by Echinococcus granulosus (for which albendazole is used). Scoleces and cestode segments are killed, but ova are not. Niclosamide is effective in the treatment of infections from small and large intestinal flukes.

Toxicity

Toxic effects are usually mild but include gastrointestinal distress, headache, rash, and fever. Some of these effects may result from systemic absorption of antigens from disintegrating parasites. Ethanol consumption should be avoided for 24-48 h.

Skill Keeper Answers: Antimicrobial Chemotherapy in Pregnancy

1. In the United States a drug is designated (by the FDA) as Pregnancy Risk Category X if the risk of its use in pregnancy is judged to be greater than any possible benefit. Such drugs have been established to cause fetal abnormalities or miscarriage in humans. This category includes the antiviral agent ribavirin and the antimalarial drug quinine. Clomiphene, ergots, ethionamide, HMG-CoA reductase inhibitors, isotretinoin, misoprostol, Premarin, and thalidomide are also category X drugs.

2. For drugs in FDA Pregnancy Risk Category D, there is evidence of human risk, but their potential benefit may outweigh such risk. In other words, they are not absolutely contraindicated in pregnancy. These include aminoglycosides (eg, gentamicin) and tetracyclines. Although they are not category D drugs, fluoroquinolones are not approved by the FDA for use in pregnancy, and many other drugs should be used with caution or avoided if alternatives are available.

Checklist

When you complete this chapter, you should be able to:

·                  List the clinical uses and the adverse effects of albendazole/mebendazole, diethylcarbamazepine, ivermectin, and pyrantel pamoate.

·                  Name the antihelminthic drug (or drugs) that (1) facilitate the actions of GABA, (2) increase calcium permeability in muscle, (3) activate nicotinic receptors, and (4) disrupt microtubule function.

·                  Describe the clinical uses and adverse effects of both praziquantel and niclosamide.



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