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Content  Introduction  Treatment of infection caused by nematodes  Treatment of infection caused by cestodes  Treatment of infection caused by trematodes  References 2

Antihelminthics  Helminthic infections are the major health problem in tropical countries and many people suffering from worm infections, worm can cause g.i.t and general symptoms.  They are also causes blood loss, nutritional deficiencies, urticaria, allergic manifestation and even intestinal obstruction. 3

 Pathogenic helminths can be divided into the following major groups:  cestodes (flatworms),  nematodes (roundworms),  trematodes (flukes)  Acanthocephala (thorny-headed worms). 4

HELMINTH INFECTIONS  Examples of worms that live in the host's alimentary canal are as follow.  Tapeworms: Taenia saginata, Taenia solium, Hymenolepis nana and Diphyllobothrium latum..  Intestinal roundworms : Ascaris lumbricoides (roundworm), Enterobius vermicularis (threadworm), Trichuris trichiura (whipworm), Necator americanus and Ankylostoma duodenale (hookworms). 5 Hookworm Tricuris tricura

The main examples of worms that live in the tissues of the host are as follow:  Flukes : Schistosoma haematobium, Schistosoma mansoni, and Schistosoma japonicum. These cause schistosomiasis (bilharzia). The adult worms of both sexes live and mate in the veins or venules of the gut wall or the bladder.  Tissue roundworms : Trichinella spiralis, Dracunculus medinensis (guinea worm) and the filariae, which include Wuchereria bancrofti, Loa loa, Onchocerca volvulus and Brugia malayi. They live in lymphatic connective tissueor mycentry of host.  Hydatid tapeworm: These are cestodes of the Echinococcus species for which canines are the primary hosts, and sheep the intermediate hosts. 6

 Most available anthelmintic drugs exert their antiparasitic effects by interference with body function like:- 1. energy metabolism, 2. neuromuscular coordination, 3. microtubular function, 4.cellular permeability. 7

TREATMENT FOR INFECTIONS CAUSED BY NEMATODES  Nematodes are long, cylindrical unsegmented worms that are tapered at both ends. Because of their shape, they are commonly referred to as roundworms.  They produce abdominal pains, diarrhea and, if many worms are present, anemia,pneumonia in lung. 8 Ascaris lumbricoids

Piperazine  MA o It acts on the musculature of the helminthes to cause reversible paralysis mediated by chloride-dependent hyperpolarization of the muscle membrane. o This results in expulsion of the worm. o Piperazine acts as an agonist at GABA- gated chloride channels on the parasite muscle. o Piperazine is administered orally and is readily absorbed from the intestinal tract. Most of the drug is excreted in the urine within 24 hours. 9

o It is used to treat infection of round worm (ascaris lumbricoides) and thread worm (enterobius vermicularis ) o Side effects  gastrointestinal distress,  urticaria, and dizziness. Neurological symptoms of  ataxia, hypotonia, visual disturbances  It should not be used in pregnant women because of the formation of a potentially carcinogenic and teratogenic nitrosamine metabolite. And renal, hepatic insufficiency. 10

levamisole  It is immunomodulating agent in cancer, auto immune disease and chronic bacterial infection.  It is a nicotinic like action stimulating and block NM junction to paralysis and death.  It is given orally is rapidly absorbed, it cross BBB. It is metabolized in liver and excreted via kidney.  Plasma half life is 4 hr.  It is used infection of round warm like ascarsis lumbricoides 11

Diethylcarbamazine  MA o It interferes with the metabolism of arachidonic acid and blocks the production of prostaglandins, resulting in capillary vasoconstriction and impairment of the passage of the microfilaria. o Diethylcarbamazine is absorbed from the gastrointestinal tract, and peak blood levels are obtained in 4 hours; the drug disappears from the blood within 48 hours. The intact drug and its metabolites are excreted in the urine 12

It is used infection caused by wuchereria bancrofti and loa loa. o Side effect o fever, lymphadenopathy, cutaneous swelling, leukocytosis, and intensification of any preexisting eosinophilia, o edema, rashes, tachycardia, and headache. o If microfilariae are present in the eye, further ocular damage may result 13

Ivermectin o Ivermectin acts on parasite-specific inhibitory glutamate-gated chloride channels that are related to GABA-gated chloride channels. o Ivermectin causes increase cl conductance, hyperpolarization of the parasite cell membrane and muscle paralysis. o At higher doses it can potentiate GABA-gated chloride channels. o It does not cross the blood-brain barrier and therefore has no paralytic action in mammals, 14

o Ivermectin is administered by the oral and subcutaneous routes. o It is rapidly absorbed. Most of the drug is excreted unaltered in the feces. o The half-life is approximately 12 hours. o it is active against roundworm, tapeworm but not hook warm. o The side effects are minimal, with purities, fever, and tender lymph nodes occasionally seen 15

Pyrantel Pamoate  MA o Pyrantel pamoate is a agonist at the nicotinic acetylcholine receptor, and its actions result in depolarization and paralysis of the helminthes muscle. o Its selective toxicity occurs primarily because the neuromuscular junction of helminthes muscle is more sensitive to the drug than is mammalian muscle. o This drug is administered orally, and because very little is absorbed, high levels are achieved in the intestinal tract. Less than 15% of the drug and its metabolites are excreted in urine. o Side effect o headache, dizziness, and drowsiness. 16

BENZIMIDAZOLES  Three benzimidazoles are in use for the treatment of helminthic infections. A.Thiabendazole B.Mebendazole C.Albendazole 17

A. Thiabendazole o Thiabendazole inhibits fumarate reductase and electron transport–associated phosphorylation in helminths. o Interference with ATP generation decreases glucose uptake and affects the energy available for metabolism. o Benzimidazole anthelmintics as a class (e.g.thiabendazole, mebendazole, and albendazole), bind selectively to -tubulin of nematodes (roundworms), cestodes (tapeworms), and trematodes (flukes). o This inhibits microtubule assembly, which is important in a number of helminth cellular processes, such as mitosis, transport, and motility. 18

o Thiabendazole is administered orally and is rapidly absorbed from the intestinal tract, with peak plasma levels achieved in 1 to 2 hours. The drug is metabolized in the liver and excreted in urine within 24 to 48 hours o Side effect o Anorexia, nausea, vomiting, drowsiness, and vertigo o occur in up to one-third of patients. Diarrhea, pruritus,rash, hallucinations, crystalluria, and leukopenia o shock, hyperglycemia, lymphadenopathy, Stevens- Johnson syndrome 19

B. Mebendazole o MA o mebendazole does not inhibit fumarate reductase. o The selective binding to nematode tubulin may inhibit glucose absorption, leading to glycogen consumption and ATP depletion. o Mebendazole is given orally; it is poorly soluble, and very little is absorbed from the intestinal tract. About 5 to 10%, principally the decarboxylated derivatives, is recovered in the urine o Abdominal discomfort and diarrhea may occur when the worm load is heavy. o It is contraindicated during pregnancy. 20

C. Albendazole  MA  Albendazole appears to cause cytoplasmic microtubular degeneration, which in turn impairs vital cellular processes and leads to parasite death.  There is some evidence that the drug also inhibits helminth-specific ATP generation by fumarate reductase.  Albendazole is given orally and is poorly and variably absorbed (5%) because of its poor water solubility. The drug is rapidly metabolized in the liver  The half life of the metabolites is 8 to 12 hours.  It is use in ascariasis, trichuriasis, enterobiasis and capallariasis.  side effects  Epigastric distress, nasea, dizziness, hepatotoxicity and bon marrow dipression. 21

TREATMENT FOR INFECTIONS CAUSE BY CESTODES  Cestodes, or tapeworms, are flattened dorsoventrally and are segmented. The tapeworm has a head with round suckers or sucking grooves.  Some tapeworms have a projection that bears hooks. This head, or scolex is used by the worm to attach to tissues. 22 Tapeworm

Niclosamide  Mechanism of Action  Niclosamide is a chlorinated salicylamide that inhibits the production of energy derived from anaerobic metabolism and inhibition of oxidative phosphorylation.  Niclosamide is not absorbed from the intestinal tract, high concentrations can be achieved in the intestinal lumen.  Adverse Effects  No serious side effects are associated with niclosamide use  some patients report abdominal discomfort and loose stools. 23

TREATMENT FOR INFECTIONS CAUSED BY TREMATODES  Trematodes (flukes) are nonsegmented flattened helminths that are often leaflike in shape.  Most have two suckers, one found around the mouth (oral sucker) and the other on the ventral surface. Most are hermaphroditic  Diarrhea, abdominal pain, and anorexia are common symptoms associated with trematode infestation. Liver flukes may cause bile duct blockage, liver enlargement, upper right quadrant pain, and diarrhea. 24

Praziquantel The neuromuscular effects of praziquantel appear to increase parasite motility leading to paralysis.  The drug increases calcium permeability through parasite- specific ion channels by protein kinase C- binding site in b sub unit of schistosome voltage gated channel, so that muscle cells of the parasite accumulate calcium leads to paralysis and death.  Praziquantel is readily absorbed (80% in 24 hours) after oral administration, with serum concentrations being maximal in 1 to 3 hours; the drug has a half-life of 0.8 to 1.5 hours. Praziquantel is excreted by the kidneys.  Side effect  gastrointestinal intolerance with nausea, vomiting, and abdominal discomfort.  This may be due to the liberation of helminth proteins from dead worms rather than any direct effect of the drug 25

Oxamniquine  MA  The drug may act by esterification and binding of DNA, leading to the death by interruption of its nucleic acid and protein synthesis.  The fluke may esterify oxamniquine to produce a reactive metabolite that alkylates parasite DNA.  Oxamniquine is given orally and is readily absorbed from the intestinal tract. Peak concentrations in plasma are obtained in about 3 hours. The drug is excreted in urine mostly as a 6-carboxyl derivative  Side effect  CNS toxicity with unsteadiness and occasionally seizures, especially in patients with a history of seizures.  It is contraindicated in pregnancy. 26

Bithionol  MA  Bithionol is a phenolic derivative whose mode of action is related to uncoupling of parasite specific fumarate reductase–mediated oxidative phosphorylation leads to death of parasites.  The drug is administered orally and is absorbed from the intestinal tract. Peak blood levels are achieved in 4 to 8 hours. Excretion is mainly by the kidneys.  Side effects  nausea, vomiting, diarrhea, headache, dizziness, urticaria, and other skin rashes 27

Choice of drugs for helminthiasis 28 noworm1 st choise2 nd choise 1Round worm Ascaris lumbricoides Mebendazole, albendazole, Piperazine, livamisole,iver mictim. 2Hook worm Ancylostoma Necator americanus Mebendazole, albendazole levamisole 3Thread worm Enterobius vermicularis Mebendazole, albendazole piperazine 4Filaria Wuchereria bancrofti, Brugia malayi Diethyl carbamazepi ne, ivermictin albendazole 5Tape worm T.Saginata T.Solium Hymenolepsis nana Praziquantel, miclosamide albendazole

References 1.Goodman LS, Hardman JG, Limbird LE, Gilman AG. Goodman and Gilman's the pharmacological basis of therapeutics: McGraw-Hill; Rang HP, Dale M. Pharmacology: Churchill Livingstone, Elsevier; page no: Tripathi KD. Essentials Of Medical Pharmacology: Jaypee Brothers Medical Publishers; 2008.page no:

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