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2.Anthelmintics

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2.Anthelmintics Anthelmintic Anthelmintic or antihelminthics are a group of antiparasitic drugs that expel parasitic worms (helminths) and other internal parasites from the body by either stunning or killing them and without causing significant damage to the host. They may also be called vermifuges (those that stun) or vermicides (those that kill). Anthelmintics are used to treat people who are infected by helminths, a condition called helminthiasis. These drugs are also used to treat infected animals. Antiparasitics that specifically target worms of the genus Ascaris are called ascaricides. Classification: Benzimidazoles: Albendazole – effective against threadworms, roundworms, whipworms, tapeworms, hookworms Mebendazole – effective against various nematodes Thiabendazole – effective against various nematodes Fenbendazole – effective against various parasites Triclabendazole – effective against liver flukes Flubendazole – effective against most intestinal parasites Abamectin (and by extension ivermectin) - effective against most common intestinal worms, except tapeworms, for which praziquantel is commonly used in conjunction for mass dewormings Diethylcarbamazine – effective against Wuchereria bancrofti, Brugia malayi, Brugia timori, and Loa loa. Pyrantel pamoate – effective against most nematode infections residing within the intestines `Levamisole Salicylanilide – mitochondrial un-couplers (used only for flatworm infections): Niclosamide Oxyclozanide Nitazoxanide – readily kills Ascaris lumbricoides,[5] and also possess antiprotozoal effects[6] Praziquantel – effective against flatworms (e.g., tapeworms and schistosoma) Octadepsipeptides (e.g. Emodepside) – effective against a variety of gastrointestinal helminths Monepantel (aminoacetonitrile class) - effective against a variety of nematodes including those resistant to other anthelmintic classes Spiroindoles (e.g. derquantel) - effective against a variety of nematodes including those resistant to other anthelmintic classes Artemisinin – shows anthelmintic activity[7] Dose: Anthelmintic Need: We know that parasitic infestation in animals makes them anaemic and weak. They can interfere with the growth of young ones. Parasitic infestation in lactating animals generally decreases milk yield. As a whole, the parasitic load in animals make them debilitated and bad looking. If an animal with worm load is seen, its skin and hair texture is not charming. General Mode of Action of Anthelmintics: i. Neuromuscular Blockers: Some of the anthelmintics have action on the neuro-muscular system. For example, piperazine acts in the similar fashion as the curare and causes paralysis of the worms, especially Ascaris. The paralysis of the worms is due to hyperpolarization of the muscle membranes. ii. Cholinomimetics: e.g. Levamisole, methyridine, morantel, pyrantel, bephenium, thenium etc. The above cited drugs affect neuromuscular system of worms acting like cholinomimetics. These agents possess functional groups similar to acetylcholine and bind to the receptors from which the acetylcholine binds. By doing so, it causes a continuous stimulatory effect. However, these are not inactivated by acetylcholine esterase. iii. Inhibitors of Glucose Transport: Some anthelmintic agents like dithiazanine which is given for canine whipworm, inhibits glucose uptake. Thus, by reducing glycogen content causes death of the worms. iv. Disruptors of Glycogen Metabolism: Schistosomicidal drug (niridazole) reduces phosphorylase phosphatase activity and increases the breakdown of glycogen reserve in worms. The death of worms is due to starvation. v. Inhibitors of Glycolysis: e.g. Arsenicals (thiacetarsamide), antimonials, (potassium antimony tartarate), stibophen etc. are organic trivalent heavy metals and bind with sulfhydryl (-SH) group. By binding with -SH they change the tertiary structure of proteins and the active site of enzymes. vi. Inhibitors of Mitochondrial Reactions: Benzimidazoles and thiophanate work in this way. For muscle contraction in works, high energy (ATP) is required which is provided after reduction of fumerate to succinate in mitochondria. The above drugs exert their action by inhibiting fumerate reductase which is required for conversion of fumerate to succinate. vii. Un-Couplers Electron Transport: Salicylanilides (clioxanide), niclosamide, oxyclozanide, rafoxanide, substituted phenols (bithionol, dinitrophenol, hexachlorophene, niclofolam, nitroxynil etc. are un-couplers of electron transport. These drugs interfere with electron transport associated with phosphorylation process which is an important biochemical process for generation of ATP. As ATP is an important source of chemical energy to parasites, the worms lack this energy and die. Properties of Ideal Anthelmintics: i) Efficacy: An ideal anthelmintic should have high level of anthelmintic activity. The efficacy is said to be good if it removes 95% of a gastro-intestinal nematodes from ruminant species. If it removes only 70% of the worm burden it is considered as a poor anthelmintic. It should have effect on both adult and larval stages of worms. If it is effective only against adult worms it is repeated to eliminate adult worms that were unaffected during the first dose. 100% removal of worm load also eliminates the source of antigenic stimulation and animal looses the acquired resistance to parasite. (ii) Wide therapeutic Index: The anthelmintic compound should possess wide therapeutic index so that minor variation in calculation of dosage should not produce any toxicity in host. Since, the parasite and host shares some of the similar metabolic reactions and it may be the target for many drugs. Anthelmintics are much safer for hosts when their mechanism of action and biochemical pathways of worms do not share mutually. (iii) Ease of Administration: It should be easily administered. Most of the anthelmintics are administered orally in empty stomach. However, some of the anthelmintics are administered parenterally e.g. Ivermectin, ancylol etc. (iv) Residue: It should be eliminated from the body without any residual problems. The anthelmintics possessing a long withdrawal time will create human health hazards after consumption of milk, meat and other animals produce. The anthelmintics having a short withdrawal time are much safer. Classification of Anthelmintics: (i) Antinematodal (ii) Antieestodal (iii) Antitrematodal Antinematodal Drugs: Drugs that act against round worms are called antinematodals. These drugs are classified as follow: I. Simple Heterocyclic compounds e.g., Phenothiazine, piperazine etc. II. Benzimidazoles e.g., Mebendazole, thiabendazole, cambendazole, albendazole, fenbendazole etc. III. Imidazothiazoles e.g. Butamisole hydrochloride, levamisole etc. IV. Tetrahydropyrimides e.g. Pyrantel and morantel. V. Organophosphorus compounds e.g. Crufomate, haloxon, coumaphos, diclorvos, trichlorfon etc. VI. Miscellaneous drugs e.g. Toluene, n-Butylchloride, tetrachloroethane, theniumclosylate, disophenol, phthalofyne, glycobiarsol, avermectins, hygromycin B. Phenothiazine: It is an old drug which was marketed as powder containing 95% pure phenothiazine (Phenovis). It was synthesized in 1885 and its anthelmintic activity was detected in 1938. Chemistry: It is chemically thiodiphenylamine. It is pale, green yellow powder, stable in dry condition and easily oxidizes when comes in contact with moisture. It is insoluble in water. Anthelmintic Spectrum: Ruminant: It has wide range of activity against GI nematodes. It possess good anthelmintic activity for the large stomach worm (Haemonchus) and nodular worm (Oesophagostomum) of cattle, sheep and goats. However, it is less effective against smaller stomach worm (Ostertagia, Trichostrongylus axei) and the hook worm (Bunostomum). It possess limited activity against roundworms of small intestine (Cooperia, Nematodirus and Trichostrongylus). It is not effective against larvae or immature round worms as well as against flukes and tape worms. Horses: Phenothiazine is 100% effective (Reffer Jone’s) against small strongyles and equine ascarids. It does not have efficacy against bots. The commercial preparations that contain piperazine and carbon disulfide along with phenothiazine are effective against ascarids, bots and strongyles in a single dose treatment. Mode of Action: Exact mechanism of action is not known. Resistant worms absorb the same quantity of phenothiazine equivalent to that of susceptible one but do not show any sign of toxicity. Therefore, the quantity of phenothiazine absorbed by the worms is not related with its mode of action. It is expected that the differences in the enzymatic system of worms are related with the mechanism of action of phenothiazine. Pharmacokinetics: Phenothiazine is converted to phenothiazine sulfoxide by the cellular enzyme of intestinal epithelium and then it is absorbed. Liver oxidizes it into two metabolites i.e. leucophenothiazone and leucothianol. The both metabolites are colorless and excreted in urine. After excretion they are oxidized in air to brown red dyes i.e. thianol and phenothiazone. The red coloration of urine should not be confused with haematuria because sometimes the owners of the animals complain the clinicians that blood is coming with urine after phenothiazine administration. Toxicity: Horses are more susceptible to phenothiazine toxicity than cattle, swine, sheep and goat but birds are resistant. It should not be used in dogs and cats because of their high susceptibility to phenothiazine. Toxicity Symptoms (Horse):
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