Anti-nematodal drugs:

• These drugs are specifically designed to act against nematode i.e. roundworms
• These drugs either inhibit special metabolic process of worm or cause the parasite to be exposed to higher concentration of drug than host cells through its pharmacokinetic properties.

Classification:

Depending on chemical structure and mode of action, antinematodal drugs are consist of following class of drugs:

1. Benzimidazole:
2. Benzimidazole: Albendazole, Tiabendazole, Fenbendazole, Mebendazole, Oxibendazole, Cambendazole, Flubendazole and Parbendazole
3. Pro-benzimidazole: Febantel, Netobimin and Thiophanate
4. Macrocyclic lactones:
5. Avermectins: Ivermectin, Doramectin, Eprinomectin, Abamectin and Selamectin
6. Milbemycins: Milbemycin oxime and Moxidectin

• Imidazothiazole: Tetramisole, Levamisole, Butamisole

1. Tetrahydropyrimidines: Pyrantel, Morantel and Oxantel
2. Organophosphorus compounds: Dichlorvos, Metrifonate, Coumaphos, Haloxon, Crufomate and Naphthalophos
3. Piperazine: Piperazine and diethylcarbamazine

• Arsenicals: Thiacetarsamide, Melarsomine, Glycobiarsol & Arsenamide
• Substituted phenols and salicylanilides: Disophenol, Nitroscanate, Nitroxinil & Closantel

1. Octaadepsipeptides: Emodepside
2. Aminoacetonitrile: Monepantel
3. Miscellaneous drugs: Phenothiazine, tetrachloroethylene, N-butyl chloride, Toluene, Thenium closylate, Phthalofyne, Dithiazamine iodide and Hygromycin B.

Benzimidazole:

• These consist of large family of broad-spectrum Antihelmintics having wide margin of safety and high degree of efficacy.
• These are heterocyclic aromatic organic compounds consisting of fusion of benzene and imidazole. They contain 1,2-diaminobenzene ring system
• These group broadly includes Tiabendazole analogues and benzimidazole carbamates. Replacement of thiazole ring of tiabendazole by methyl carbamates produces newer generation of benzimidazole carbamates which have broader spectra, high potencies, complex metabolic pathways and slower rate of excretion.

Mechanism of action:

• MOA of benzimidazole depends on contact time with parasite. So, it is useful in divided dose and more effective in ruminants and horses than monogastric animals as drug passage is slow through rumen and caecum, which provides greater contact time
• It mainly produces its antihelmintic action by binding to β-tubulin and inhibiting polymerization or assembly into microtubules
• Other mechanism of action includes inhibition of mitochondrial fumarate reductase enzyme, blocking of glucose transport and uncoupling of oxidative phosphorylation. Blocking of these process causes inhibition of supply of energy to parasites. As a result, antihelmintic action is achieved.
• They also induce sterility by inhibiting egg production and uncoupling oxidative phosphorylation.

Normally helminthic microtubule is made up of polymerization of α and β tubulin. In this process, polymerization occurs at one end and depolymerization occurs at another ends.

Benzimidazole binds to β-tubulin and inhibits polymerization of microtubule

Continual depolymerization of microtubule at another end without addition of α and β subunits leads to breakdown of microtubule

Disruption of integrity and transport functions of cell within parasite and blocks cell division

As a result, parasites dies and antihelmintic action is produced

# Tiabendazole (Thiabendazole):

• It was first benzimidazole antihelmintics introduced in 1961.
• It is broad-spectrum prototypic drug of this class
• It is active against nematodes, fungi and mites.

Antihelmintic spectrum:

• It is broad-spectrum antibiotic with activity against all major GI nematodes of sheep, cattle, goats and horses.
• Active against Haemonchus, Trichostrongylus, Bunostomum, Ostertagia, Nematodirus, Oesophagostomum and Chabertia species in ruminants.
• In horses it is active against Strongylus, Oesophagodontus, Posteriostomum, Cyathostomum, Oxyuris, Parascaris and Cyclicocylos

Pharmacokinetics:

• Absorbed rapidly after oral administration
• Reaches peak plasma concentration after 2-7 hours
• Distributed throughout the body tissues
• Excreted mainly in urine and smaller amounts in faeces.

Side effects/Adverse effects:

• Vomiting, Diarrhoea, Hair loss, Lethargy in dogs
• In other species, it is generally well tolerated

Contraindications and precautions:

• High doses should be avoided in animals, particularly dogs
• It is safe during pregnancy

Clinical use:

• Mainly used in treatment of helminthiasis by susceptible parasites.
• In dogs, it is used only systemically for treatment of Strongyloides and Filaroides.

Dose:

Dogs: 50 mg/kg, PO, as single dose

Cattle: 50-100 mg/kg, PO, as single dose

Sheep, goats & swine: 50-75 mg/kg, PO, as single dose

Horses: 50 mg/kg, PO, as single dose

Poultry: 250-500 mg/kg, PO, as single dose; may be repeated in 10-14 days

# Albendazole:

• It is also broad-spectrum methyl carbamate antihelmintics
• It is widely used in veterinary medicine for treatment of nematode and trematode infections in large animals

Antihelmintics spectrum:

• Active against Ostertagia, Haemonchus, Trichostrongylus, Cooperia, Bunostomum and Oesophagostomum.
• Also active against lungworm (Dictyocaulus), tapeworm and flukes

Pharmacokinetics:

• It is well absorbed (~50%) after oral administration
• Rapidly converted to sulphoxide metabolite after oral administration which mainly produces antihelmintic action
• Widely distributed in body including CNS
• Both parent drug and its active and inactive metabolites are excreted through urine.

Side effects/Adverse effects:

• Well tolerated at recommended dose
• Dogs may develop anorexia and myelosuppression
• In cats, it may show lethargy, depression, anorexia, weight loss and neutropenia in high doses or prolonged administration

Contraindications and precautions:

• In pregnancy due to its teratogenic effect

Indications:

• In treatment of nematodal infections in large animals
• In dogs, it is used to treat Filaroides infection
• In cats, it is used against Paragonimus kellicoti.

Dose:

Cattle: 7.5 mg/kg, PO

Sheep: 5 mg/kg, PO

Goats: 10mg/kg, PO

Swine: 5-10 mg/kg, PO

Horses: 25 mg/kg, 2 times daily for 5 days

Dogs: 25-50 mg/kg, PO, 2 times daily for 5 day, repeated in 21 days

Cats: 25,g/kg, PO, 2 times daily for 10-21 days

Pro-benzimidazole:

# Febantel:

• It is benzimidazole pro-drug which is metabolized to fobendazole and oxibendazole in vivo

Mechanism of action:

Febantel gets converted into fobendazole in vivo

Fobendazole binds to β-tubulin and inhibits polymerization of microtubule

Continual depolymerization of microtubule at another end without addition of α and β subunits leads to breakdown of microtubule

Disruption of integrity and transport functions of cell within parasite and blocks cell division

As a result, parasites dies and antihelmintic action is produced

Antihelmintic spectrum:

• It is active against small and large Strongyloides, ascarids & pinworms in horses
• Effective against hookworms, roundworm, whipworm and tapeworm in dogs
• Effective against A. tubeforme and Toxocara cati in cats
• In ruminants, it may help to remove abomasal and intestinal nematodes, lungworms and trematodes.

Pharmacokinetics:

• Readily absorbed from GI tract
• Rapidly metabolized to febendazole, oxibendazole
• Peak plasma concentration occur 6-12 hours after oral administration in sheep and 12-24 hrs in cattle.

Side effects/Adverse effects:

• At high dose or prolonged administration, transient salivation, diarrhoea, vomiting and anorexia seen in dogs and cats
• Combination with praziquantel in horses produces salivations, mouth irritations, diarrhoea and colic
• Foetal abnormalities, increased abortion in pregnant animals

Contraindications and precautions:

• In pregnant animals

Clinical use:

• For removal of GI roundworms in horses, ruminants, pigs and pigeons
• For treatment of hookworm, whipworms and tapeworms in dogs & cats.

Dose:

Cattle: 7.5mg/kg, PO, as single dose

Horses: 6 mg/kg, PO, as single dose

Sheep & swine: 5 mg/kg, PO, as single dose

Pigeons: 30 mg/kg, PO

In combination with praziquantel

Dogs & cats (>6 months): 10mg/kg (febantel) + 1mg/kg (praziquantel), PO, for 3 days

Avermectins:

• These are group of closely related antibiotics, isolated from Streptomyces avermitilis
• Highly potent and shows activity against wide range of parasites from nematodes to ectoparasitic arthropods
• No activity against Platyhelminthes.

Mechanism of action:

Avermectin binds to specific glutamate-gated Cl^– channels located in nerve cells of parasite

Opening of glutamate-gated Cl^– channels

Opening of channels promotes chloride ion influx

These influx cause hyperpolarization of nerve cell and inhibit initiation or propagation of action potential

Paralysis of targeted parasite which ultimately dies

* Since cestodes and trematodes lack these channels, they donot show activity against these parasites

* Since it cannot cross BBB and reaches CNS as well as mammals donot contain these channels and low affinity of drug to mammalian GABA receptors, drug becomes safe in mammals

Antihelmintic resistance:

• Resistance develops due to alteration in genes encoding ATP-dependent P-glycoprotein transporters which bind avermectin or changes component of glutamate-gated Cl^–

# Ivermectin:

• It was first commercially available macrolide antihelmintics
• It is semi-synthetic agent derived from natural avermectins
• It is highly lipophilic

Antihelmintic spectrum:

• Effective against large and small Strongyles, Ascarids, Pinworms, Hairworm, Bots, Lungworms and Intestinal threadworms in horses.
• Useful against intestinal roundworms and lungworms in cattle and swine.
• Effective against immature Dirofilaria immitis in dogs but less effective on adult worms
• Also possess ectoparasiticide action against cattle grub, sucking lice, mites and horn flies.

Pharmacokinetics:

• In simple stomach animal, it is well absorbed (>90%) from GI tract but in ruminants absorption is moderate (25-30%) due to inactivation of drug in rumen
• SC administration leads to higher bioavailability but absorption is slow
• Well distributed into most tissues except CNS. But in collie breeds these penetrate into CNS in huge amount. So, they are susceptible to toxicity
• Partly metabolized in liver by oxidation and excreted both unchanged and changed in faeces.
• Long-terminal half-life; dogs= 2 days, cattle= 2-3 days, sheep= 2-7 days and swine= 0.5 days

Side effects/Adverse effects:

• Swelling and pruritus in horses at ventral midline due to hypersensitivity reaction to dead parasite
• Toxicities in collie, Australian shepherd & Shetland sheep dog manifested clinically by mydriasis, salivation, ataxia, tremors, paresis, stupor, recumbency and coma.
• Lethargy and anorexia in birds

Contraindications and precautions:

• In collie or collie-mixed breeds
• In calves less than 12 weeks and puppies <6 weeks
• Injectable product should be administered SC only
• In horses, it should be given by oral route only

Clinical uses:

• Commonly used as endectocide in veterinary medicine
• As ectoparasiticide against mange, mites, lice, grubs and horn flies
• Against GI roundworms and lungworms in horses, ruminants and pigs
• Against heartworm as preventive measure in dogs and cats.

Dose:

For parasitic infection

Dogs: 0.2-0.3 mg/kg, SC or PO, repeated in 14 days

Cats: 0.4 mg/kg, SC

Horses: 0.2 mg/kg, PO

Cattle: 0.2 mg/kg

Sheep: 0.2 mg/kg, PO or SC

Goats: 0.2 mg/kg, PO

Swine: 0.3 mg/kg, SC

Birds: 0.2-0.4 mg/kg, PO, IM or SC

Imidazothiazoles:

Levamisole:

• It is 1-isomer of di-tetramisole, belonging to class of synthetic imidazothiazoles derivatives
• It has greater safety margin
• It is also an immunomodulator

Mechanism of action:

These drugs bind to L-subtype nicotinic acetylcholine receptor in nematode muscle

This causes the sustained muscular contraction of reproductive muscles in males

Increased ability of male to copulate and muscular paralysis in parasite

Lose their grip on intestinal wall

Removed from the body in faeces

• They also block fumarate reductase and succinate oxidase which interferes with carbohydrate metabolism at high dosage.

Antihelmintic spectrum:

• It is effective against adult and larval GI roundworm and lungworms in cattle, sheep, goat, swine and poultry
• In swine, it is active against Ascaris, Lungworm, nodular worms and kidney worms
• In dogs, it is effective against microfilariasis
• No activity against tapeworms, flukes and protozoa

Parasitic resistance:

• Resistance is due to loss of cholinergic receptors in susceptible parasites

Pharmacokinetics:

• Well absorbed from GI tract after oral administration and through skin after topical application
• Levamisole by SC route is absorbed efficiently, and peak plasma concentration is achieved in <1 hour
• After absorption, it is well distributed throughout body
• Partly metabolized in liver and excreted in urine
• Plasma elimination half-lives varies with species; cattle= 4-6 hrs, dogs= 1.8-4 hrs, swine= 2.5-7 hours

Side effects/Adverse effects:

• Narrow safety margin but well tolerated at recommended dosages
• Salivation, constriction of pupil, muscle tremor, excitation, ataxia, colic, diarrhoea, urination, dyspnoea, transient coughing and collapse
• Pain and inflammation at injection site

Contraindications and precautions:

• In weak, severely debilitated and lactating animals
• It should be used cautiously in patients with hepatic or renal impairment
• As it is related with idiosyncratic reactions and serious blood disorders in small number of people, operators who administer or handle levimasole should wear protective clothing.

Clinical uses:

• As deworming agent in pigs, cattle, sheep
• Also used occasionally in dogs as a microfilaricide

Dose:

Cattle: 7.5 mg/kg, SC or PO, as single dose

Sheep: 7.5 mg/kg, SC or PO, as single dose

Swine: 8 mg/kg, PO, in feed or drinking water

Dogs: 5-8 mg/kg, PO

Poultry: 25-50 mg/kg, PO

Pigeons: 20 mg (total), PO

Tetrahydropyrimidines:

Pyrantel:

• It is broad-spectrum antihelmintics introduced in 1950

Mechanism of action:

Acting as neuromuscular depolarizing agent they activate nicotinic cholinergic receptor

Sudden contractions followed by paralysis of helminths

Parasite loses its grip from intestinal wall

Expelled slowly from body in faeces

Antihelmintic spectrum:

• It has high efficacy against adult GI nematodes and larval stages
• Active against Strongyloides, ascarids and pinworms in horses
• Active against Toxocara canis, A. caninum & stomach worm in dogs
• In cattle, sheep and goats, they are effective against Haemonchus, Ostertagia, Trichostrongylus, Nematodirus, Chabertia, Cooperia and Oesophagostomum species
• No activity against cestodes and trematodes

Pharmacokinetics:

• Pyrantel pamoate is poorly absorbed from GI tract
• Pyrantel tartarate is absorbed more rapidly with peak plasma concentration achieved in 2-3 hrs in dogs and swine after dosing.
• After absorption, they are rapidly metabolized and excreted in faeces and urine

Side effects/Adverse effects:

• Well tolerated at recommended dosage
• Emesis in dogs & swine
• Ataxia, tachycardia, profuse sweating
• Safe in young puppies, pregnant and lactating animals

Contraindications and precautions:

• It should not be administered in weak and severely debilitated patients
• In foals less than 4 weeks
• Safe for use in pregnancy and nursing mother

Drug interactions:

• It should not be combined with tetramisole/levimasole, organophosphorus compounds.
• Piperazine antagonize action of pyrantel

Clinical use:

• In treatment of hookworm, roundworm
• Whipworms, Strongylus treatment in horses

Dose:

Horses: 6.6 mg/kg, PO

Dogs & cats: 5 mg/kg, repeated in 3 weeks

Swine: 22 mg/kg (pyrantel tartarate), PO

Birds: 10 mg/kg, PO, repeated in 10 days

Piperazines:

• Cyclic secondary amine antihelmintics
• Available commercially in a variety of salts including citrate, adipate, phosphate, hexahydrate, chloride, sulphate and dihydrochloride

Mechanism of action:

Interacts with GABA receptor as agonist

Increased chloride conductance at nerve membrane of parasite

Membrane hyperpolarization and reduced excitability at neuromuscular junction

Muscle relaxation and flaccid paralysis

Parasite lose their grip on intestinal wall and expelled from body by intestinal peristalsis

Antihelmintic spectrum:

• It has narrower spectrum of action
• Active against ascarids and nodular worms in all species
• Little activity against whipworms and tapeworms
• Mature worms are more susceptible

Pharmacokinetics:

• Rapidly absorbed from G.I tract after oral dosing
• Some are metabolized in liver and 30-40% drug excreted unchanged in urine

Side effects/Adverse effects:

• GI disturbances and ataxia in dogs & cats
• Massive overdosage results in weakness, dyspnoea, muscular fasciculation, ataxia, hypersalivation, depression, slow pupillary response leading to paralysis and death

Contraindications and precautions:

• In chronic liver or kidney disease patients
• In patients with GI hypomotility
• May provoke seizures in patients with pre-existing seizure
• Accurate dosing should be carried out in small kittens & puppies

Drug interactions:

• They should not be combined with pyrantel or morantel due to antagonistic action.
• Piperazine and phenothiazine may precipitate seizures if used concomitantly

Clinical use:

• For treatment of ascarids in dogs, cats, horses, swine and poultry

Dose:

Dogs & cats: 80-100 mg/kg, PO

Cattle, sheep and goats: 110 mg/kg, PO

Horses: 200 mg/kg, PO

Pigs: 250-300 mg/kg, PO

Poultry: 250 mg/kg, PO

Birds: 100-500 mg/kg, PO

Arsenicals

Thiacetarsamide:

• It is organic arsenical compound

Mechanism of action:

Exact mechanism is not known clearly. But it is believed that it modulates glucose uptake and metabolism, inhibit glutathione reductase and alteration of structure and function of the surface of intestinal epithelium of parasite. All these results in death of susceptible organism and removed  through body slowly.

Antihelmintic spectrum:

• Effective against adult heartworms only

Pharmacokinetics:

• It is administered by IV route for treatment of adult heartworms
• After IV administration, it is widely distributed in the body
• Rapidly metabolized in liver and excreted in bile and also in urine
• Elimination half-lives is of about 45 minutes.

Side effects/Adverse effects:

• Vomiting
• Hepatotoxicity
• Nephrotoxicity
• Thrombocytopenia
• Thromboembolic pneumonia with signs of coughing, dyspnoea, haemoptysis, fever and lethargy.

Contraindications and precautions:

• In patients with impaired hepatic, renal or cardiopulmonary functions
• Animals receiving therapy should be provided full rest with restricted activity to reduce chances of pulmonary emboli
• Care should be taken to avoid perivascular leakage

Drug interactions:

• Glucocorticoids decrease the efficacy of thiacetarsamide.

Clinical uses:

• It is exclusively used for the treatment of adult Dirofilaria immitis.

Dose:

Dogs & cats: 2.2 mg/kg, IV, 2 times daily for 2 days

Miscellaneous drugs:

Phenothiazine:

• It is old drug discovered in 1938.

Mechanism of action:

• Not well known
• Reported to inhibit enzymes involved in carbohydrate metabolism
• High dose may inhibit cholinesterase enzyme in susceptible parasites

Antihelmintic spectrum:

• Effective against Strongylus, Trichostrongylus, Trichonema and Trichodontophorus
• In ruminants, it is effective against Haemonchus, Oesophagostomum and Ostertagia
• No activity against cestodes and trematodes

Pharmacokinetics:

• GI absorption is incomplete and erratic
• Unabsorbed portion (~50%) is responsible for antinematodal action
• After absorption, they gets converted to phenothiazines sulphoxide in intestine which reaches liver. In liver, it is again metabolized to two dyes- phenothiazone and thionol, which are excreted in urine and milk.

Side effects/Adverse effects:

• Narrow margin of safety
• Dullness
• Weakness, anorexia, oliguria, colic, constipation, fever, tachycardia and signs of hemolysis in all species except sheep & goat
• Photosensitization in calves and lambs

Contraindications and precautions:

• In weak, anemic, and emaciated animals
• It should not be used in pregnant animals or lactating animals
• In young calves, lambs, foals

Clinical use:

• Primarily used in treatment of ruminants for susceptible GI worms

Dose:

Cattle: 20-60 g (total), PO

Sheep: 5-20 g (total), PO

Horses: 10-30 g (total), PO