Anthelmintics

 

                                                                          Anthelmintics

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Anthelmintics (or dewormers) are drugs that are used to either kill (vermicidal) or expel (vermifuge) the parasitic worms or helminths (categorized into roundworms, tapeworms and flatworms) that inhabit GI tract and other tissues and organs of livestock. Animals suffering from worm infestation appear to be debilitated, emaciated and anemic. There may be reduced productivity (milk, egg and meat production) and poor weight gain despite good appetite. Even sometimes damage to vital organs and intestinal or lymphatic obstruction may also occur. The following table enlists the common helminth parasites of veterinary importance.

 

Common helminth parasites of veterinary importance
Roundworms (Nematodes)	Ancylostoma caninum, Ascaridia galli, Dictophyma renale (Kidney worm), Dictyocaulus viviparus (Lung worm), Dirofilaria immitis (Heart worm), Haemonchus contortus, Heterekis gallinarum, Oxyuris equi, Parascaris equorum, Strongylus vulgaris, Syngamus trachea, Thelazia lacremylis (Eye worm), Toxocara canis, Toxocara cati.
Tapeworms (Cestodes)	Diphyllobothrium latum, Dipylidium caninum, Echinococcus granulosis, Moniezia expansa, Taenia ovis.
Flatworms (Trematodes)	Dicrocoelium dendriticum, Fasciola hepatica, Gastrodiscus aegypticus, Paragonimus westermani, Parampistomum cervi, Schistosoma nasalis.

 

Anthelmintics are commonly formulated as suspensions (meant for drenching) however some anthelmintics are also available in the form of tablets, pastes (applied over the gums, in case of Ivermectin for horses) and injectable solutions. Anthelmintics should be administered on the basis of careful diagnosis of worm infestation (by means of faecal examination or clinical signs manifested by the animal). And indiscriminate use of anthelmintics should be strictly discouraged to avoid the occurrence of drug resistance. Moreover many anthelmintic drugs are released into the milk of lactating animals which indicates that an optimal withdrawal period should be followed.

 

1. Benzimidazoles: They constitute the most frequently used group of broad spectrum vermicidal drugs. Thiabendazole, Albendazole, Fenbendazole, Oxfendazole, Mebendazole and Triclabendazole are included in this group. Some Benzimidazoles are available in the form of pro-drugs (such as Febental and Netobimin) that are converted to active Benzimidazoles after their in-vivo metabolism. Febental is metabolized in-vivo to Fenbendazole and Oxibendazole while Netobimin is converted to Albendazole.

Mode of action: Benzimidazoles bind to β-tubulin (a structural protein) and block the polymerization of tubulin into microtubulin. Continual depolymerization at the other end leads to complete breakdown of microtubules (normally polymerization of tubulin occurs at one end and depolymerization occurs at the other end) thereby disrupting the integrity and transport functions of cells within the parasite and blockage of cell division. They also block glucose transport in target parasites by inhibiting the action of mitochondrial fumerate reductase enzyme.

Anthelmintic spectrum: Benzimidazoles are broad spectrum anthelmintic drugs with excellent efficacy against all helminth endoparaistes (Nematodes, Trematodes and cestodes) of domestic animals and humans. Triclabendazole is very effective against all stages of Fasciola from day old to adult. Unlike other Benzimidazoles, Triclabendazole has no anticestodal and antinematodal action. Fenbendazole is also effective against Giardia infection in dogs. Thiabendazole also possesses antipyretic, anti-fungal, anti-inflammatory and analgesic actions but it is less effective against lung-worms. Albendazole is widely used for the treatment of Hydatidosis, Cysticercosis and other intestinal helminth infections in humans. The antiparasitic action of Benzimidazoles depends upon their contact time with parasites rather than the dose. Therefore they are more useful in divided doses than a single dose and are more effective in ruminants and horses than simple stomach animals (due to slow passage of drug through rumen and caecum which provides longer contact time). Acquired resistance to Benzimidazoles usually develops due to alteration in β-tubulin structure that reduces the affinity for binding to Benzimidazoles.

Adverse effects: Thiabendazole can occasionally cause vomiting and diarrhea in dogs (Dachshands are more susceptible). Oxfendazole, Albendazole, Mebendazole and Febantel are minimally teratogenic in sheep, whereas Fenbendazole and Mebendazole are not.

 

2. Macrocyclic lactones: Macrocyclic lactones are divided into two categories i.e., Avermectins (including Ivermectin, Doramectin, Abamectin and Selamectin) and Milbimycins (which include Moxidectin and Milbemycin oxime). Macrocyclic lactones are the antibiotics produced by streptomyces and Avermectins are isolated from streptomyces avermitilis.

Mode of action: Their binding to Glutamate receptors (associated with Cl^- channels) triggers chloride ion influx (as a result of opening of Cl^- channels) that causes hyperpolarization of parasite neuron and ultimately leads to paralysis and death of target parasites (nematodes and arthropods). Avermectins also bind to GABA-gated Cl^- channels and cause hyperpolarization; however its physiological consequences are less significant.

Pharmacokinetics: Ivermectin is well absorbed (>90%) from GIT after oral administration in simple stomach animals. In ruminants the ruminal inactivation reduces the bioavailability to only 25-30%. Ivermectin in faeces or soil degrades at much more slower rate and thus can suppress the larvae of some dung-breeding insects. The injectable preparations of Ivermectin should be administered only through S/C route in species other than horses (in which it is given exclusively through oral route).

Anthelmintic spectrum: They are known as endectocides as they are active against endoparasites (including nematodes, lung worms and immature heart worms) as well as ectoparasites (like cattle grubs, mange mites, lice and horn flies). They have no activity against cestodes and trematodes due to lack of glutamate-gated Cl^- channels in these parasites.

Adverse effects: Collie breed of dogs allow more penetration of Ivermectin to CNS (than any other breed or species) and are thereby more susceptible to Ivermectin toxicity (manifested by ataxia, salivation, mydriasis, tremors, paresis, recumbency and coma). Intravenous administration of Physostigmine can be helpful to treat Ivermectin toxicity in dogs. Selamectin, Moxidectin and Milbemycin oxime are safe for collie dogs. Hypersensitivity reaction to dead parasites (swelling and pruritis at the ventral midline) can occur in horses about 24 hours post administration of Ivermectin.

 

3. Imidathiazoles: Levamisole,Tetramisole and Butamisole are common members of this group.

Mode of action: Imidathiazoles act as autonomic ganglionic stimulants (cholinomimetics) and cause activation of parasympathetic nervous system. This leads to sustained muscle contraction and subsequent paralysis in nematodes. At high doses they interfere with carbohydrate metabolism of parasites by blocking fumerate reductase and succinate oxidase enzymes. They also possess immuno-stimulatory action as they stimulate cell-mediated immunity by increasing the differentiation of T-lymphocytes. Because of their different mechanisms they are also effective against benzimidazole-resistant parasites. Parasitic resistance appears to be associated with progressive loss of cholinergic receptors. These drugs potentiate the organophosphate intoxication.

Anthelmintic spectrum: Being broad spectrum nematocidal drugs, the Imidathiazoles are effective against adult as well as larval GI round worms, lung worms, whip worms, hook worms, heart worm (dogs) and kidney worms but not effective against protozoa, tapeworms and flatworms.

Adverse effects: Clinical signs of toxicity include both nicotinic and muscarinic cholinergic signs like hypersalivation, miosis (reduction of papillary diameter), frequent urination, diarrhea, broncho-constriction, muscle tremors and death (from asphyxia due to respiratory muscle paralysis). Horses and dogs are more susceptible to adverse effects. Intoxication can be treated with Atropine (cholinergic blocker) and Hexamethonium (ganglionic blocker).

 

4. Tetrahydropyrimidines: Pyrentel, Morentel and Oxantel are important drugs belonging to this category.

Mode of action: They Act as depolarizing neuromuscular blockers in target parasites, thereby paralyzing the susceptible organisms which are later on slowly expelled from the host body. Co-administration of Piperazine will antagonize the action of these drugs by causing hyperpolarization and flaccid paralysis. Pyrentel also inhibits acetylcholinesterase enzyme and therefore acts like acetylcholine. Morentel is capable to block fumerate reductase enzyme in some nematodes (e.g., Haemonchus spp.)

Anthelmintic spectrum: They are active against adult and larval nematodes residing in the lumen or on the mucosal surface but are less effective against the larvae that dwell inside the mucosa (e.g., arrested osteretagia larvae). They have no action over cestodes (except when used at high doses in horses) and trematodes. Oxantel has a narrow anti-nematodal spectrum and is effective only against whipworms.

Adverse effects: These agents are safe for use during pregnancy and lactation. Emesis may sometimes occur in dogs receiving therapeutic doses of Pyrentel.

 

5. Organophosphates: Organophosphates represent an important class of drugs that are frequently used against parasitic infestation in domestic animals. Trichlorfon, Dichlorvos and Coumaphos are common drugs included in this category.

Mode of action: They inhibit acetylcholinesterase enzyme (and thus indirectly enhance the level of acetylcholine) in susceptible helminthes leading to interference with parasite neuromuscular transmission and subsequent paralysis.

Anthelmintic spectrum: They are occasionally used to treat helminth infestation in horses (bots, strogyloids, ascarids) and dogs. Dichlorvos is less effective against ruminant nematodes and is not safe in cattle and poultry but Trichlorfon is active against some GI nematodes of ruminants. Trichlorfon is not effective against migrant larvae, tapeworms and flukes. Organophosphates possess narrow margin of safety and have been replaced by much safer and broad spectrum anthelmintics. Presently most of their preparations are meant for the treatment of ectoparasitic infestation in livestock.

Drug interactions: Organophosphates should not be co-administered with anti-cholinesterase agents, muscle relaxants, aminoglycosides and imidathiazoles.

Adverse effects: Organophosphate intoxication commonly occurs in dogs and other animals as a result of inappropriate administration or accidental overdosage. However certain precautionary measures (such as application of muzzle to avoid the licking of topically applied drug) can help to minimize the occurrence of toxicity. Three types of systemic signs are produced as a result of Organophosphate poisoning; muscarinic signs (salivation, lacrymation, and diarrhea), nicotinic signs (muscle tremors and respiratory paralysis) and nervous signs (hyperexcitation, ataxia and seizures). Treatment can be anticipated through the use of specific antidote, atropine (cholinergic antagonist) and an enzyme reactivator such as Pralidoxime.

 

6. Isoquinolones: This group is represented by only one important drug, Praziquantel.

Mode of action: Praziquantel probably increases the cell membrane permeability causing rapid calcium influx that leads to an instantaneous contraction and spastic paralysis of parasites. The affected worms loose grip over the intestinal mucosa and are expelled. Praziquantel also produces irreversible focal destruction of protective integument. The combined effect of paralysis and integumental destruction allows easy attack by the host’s proteolytic enzymes causing either complete or partial disintegration of worms in GI tract. Therefore whole tapeworms are very rarely passed in the feaces of treated animals.

Anthelmintic spectrum: Praziquantel is primarily a broad spectrum anticestodal drug but it is also used as flukicide against lung, gut, blood and liver flukes in dogs. However it has no activity against nematodes and hydatid cysts.

Adverse effects: Praziquantel is the safest anticestodal drug available for clinical use. It exerts no teratgenic or embryotoxic effects and does not affect reproductive performance. Hence it is considered safe for use in pregnant animals.

 

7. Salicylanilides: Niclosamide, Oxyclozanide and Refoxanide are included in this category.

Mode of action: They appear to act by inhibiting mitochondrial oxidative phosphorylation and interfering with the anaerobic ATP generation by the susceptible parasites.

Anthelmintic spectrum: Niclosamide is primarily used as an anticestodal drug however it also has some activity against some intestinal flukes such as Paramphistomum in ruminants. Oxyclozanide is mainly effective against adult flukes. Refoxanide is active against flukes (adult and immature), blood sucking nematodes (e.g., Haemonchus) and all parasitic larval stages of sheep nasal bot (Oestrus ovis).

Adverse effects: As Niclosamide is minimally absorbed from GI tract, no systemic toxicity occurs at normal therapeutic doses and it has no teratogenic or embryotoxic effects. Refoxanide has a long withdrawal period of 28 days so it is not used in lactating animals.

 

8. Substituted Phenols: This group includes Nitroxynil, Niclofolan and Bethionol.

Mode of action: They uncouple the mitochondrial reactions involved in electron transport chain and cause the death of target parasites through ATP depletion.

Anthelmintic spectrum: They are mainly active against mature Fasciola hepatica, but Nitroxynil is also used against Haemonchus, Oestrus ovis and Syngamus trachea. Nitroxynil and Niclofolan are not used orally (can be used parentrally i.e., S/C or I/M/) in ruminants due to their rapid metabolism and inactivation in the rumen.

Adverse effects: Nitroxynil stains wool and hair yellow, so care should be taken while administering this drug to sheep. High doses of substituted phenols may produce classical signs of uncoupled phosphorylation including hyperthermia, hyperventilation, convulsions and ultimately death. They should not be used in dairy animals as they pass into milk.

 

9. Sulphonamide derivatives: Clorsulon is a Sulphonamide derivative that possesses significant anthelmintic action.

Mode of action: Clorsulon inhibits 3-phosphoglycerate kinase and phosphoglyceromutase enzymes in the glycolytic pathway of target parasites. This deprives the parasites of their main source of metabolic energy.

Anthelmintic spectrum: Clorsulon is active against adult and immature (at high doses) Fasciola hepatica. It is less effective against Fasciola magna and ineffective against Paramphistomum. Clorsulon is often combined with Ivermectin in S/C injectable formulation for simultaneous treatment of Fasciola and nematode infection in cattle.

Adverse effects: Clorsulon has no embrytoxic, mutagenic or carcinogenic effects however it is not recommended in lactating animals due to its passage into milk.