**1. Introduction**

Antiparasitic chemotherapeutics can be categorized as anthelmintics, ectoparasiticides (insecticides and acaricides), and antiprotozoals. Anthelmintics are those agents used to destroy worms and are used as anticestodal, antinematodal, and antinematodal agents [1].

The use of chemical agents against nematodes traced back to the 1990s and those agents were having less effectiveness. Chemicals used for nematode destruction were arsenic compounds, cupric sulfate, nicotine, Chenopodium oil like alkaloids. These chemical compounds were found less effective and more toxic for livestock. Synthetic drug phenothiazine antinematodal characteristics were first reported in the United States and were used as broad-spectrum medicine for nematode treatment in horses, ruminants, and chickens. Phenothiazine is removed from the therapeutic inventory in many countries [1].

From that time scientists were trying to produce an ideal anthelmintic drug that could be used as broad-spectrum dewormers and result in the use of organophosphorus compounds, imidazoles, and tetrahydro pyrimidines. Thiabendazole (TBZ) was developed in 1961 after two decades, and this drug is having high efficiency and safety and broad-spectrum. It was the first-generation benzimidazole group and used against a wide range of hosts, i.e., goats, poultry, sheep, cattle, pigs, horses, and humans against gastrointestinal nematodes, and it shows ovicidal, larvicidal, and adulticidal activities. After TBZ's success, it was planned to structurally modify it toward evolving drugs with excellent properties. Levamisole was discovered in 1966 and was marketed with the name of hydrochloride (HCL) salt having broad-spectrum antinematodal activities and immunomodulator effects [2].

Macrocyclic lactone derivatives including ivermectin (IVM) were discovered in 1981 broad-spectrum insecticidal activities. After this in 2009 after 28 years, monepantel was commercially released [3]. Broad-spectrum antinematodal synthetic compounds are divided into four major groups, i.e., macrocyclic lactone derivatives including milbemycins/ivermectin, benzimidazole/pro-benzimidazole group, tetrahydro pyrimidines group including morantel, pyrantel tartrate, and imidazothiazoles group including tetramisole and levamisole [1].

Commonly used chemotherapeutic groups are briefly reviewed in this review.

### **2. Benzimidazoles/pro-benzimidazoles and their mode of action**

Compounds of this group are metabolized in the body and activate BZ metabolites. Members of this group are oxfendazole, ricobendazole, albendazole, thiabendazole, mebendazole, triclabendazole, oxibendazole, cambendazole, and other chemicals belonging to pro-benzimidazole, i.e., thiophanate, febantel, and netobimin [1].

Benzimidazole is effective against adult nematodes in ruminants and also has ovicidal and larvicidal activities. Some benzimidazole also exhibits anti-trematode and anticestodal activities. They are used in various hosts such as bovine, canine, equine, ovine, feline, reptiles, caprine, birds, and human species. In the case of humans, thiabendazole, mebendazole, and albendazole are used. They are having low toxicity and in some cases can be drenched 10 times than the calculated standard dose rate [2, 4].

All members of this group are having the same mode of action and disturb the energy metabolism of parasitic nematodes through binding with tubulin protein (alpha and beta molecules). This protein is present in plasma and microtubules and forms heterodimers and constructs blocks in polymeric microtubules [1]. Microtubules formation is a dynamic process affected by tubulin ring polymerization and depolymerization. Microtubules play an important role in cell division, energy metabolism, shape, and transport of substrate and protein assemblage. Benzimidazole group members bundle with β-tubulin, and this complex integrates *Anthelmintic Drug Resistance in Livestock: Current Understanding and Future Trends DOI: http://dx.doi.org/10.5772/intechopen.104186*

#### **Figure 1.**

*Illustration of four different mechanisms of action by benzimidazoles against GI parasites.*

at the propagating ends of the microtubules and inhibits the assemblage of extra microtubules. This whole process is known as capping [5–7].

They cause parasite undernourishment (due to failure in glucose uptake, the proliferation of microtubules, and protein secretion), reduction in acetylcholinesterase enzyme secretion, reduction in carbohydrate catabolism through fumarate reductase enzyme. Histological investigation of benzimidazole pharmacodynamics also reports their role in disturbance of microtubule aggregation in nematodes at those concentrations that do not influence mammalian cells (**Figure 1**) [1, 6, 8].

### **3. Imidazothiazoles and their mode of action**

Imidazothiazoles consist of two drugs, i.e., tetramisole and levamisole HCL (LEV). Levamisole is a Levo isomer and has true antinematodal activity while tetramisole is a mixture of Levo and destroys forms. That is why the calculated dose of levamisole is half that of tetramisole.

Levamisole is mostly used in goats, sheep, swine, and cattle while in the case of horses, it is contraindicated. This drug is having potency against both mature and immature stages. That's why the calculated dosage of LEV is half that of tetramisole with a safety index of twice.

In sheep, goat, cattle, and swine, LEV is administrated, and in horses, mostly it is contraindicated. In several mature and immature stages of alimentary tract nematodes and lungworms, LEV has shown great potential. Whereas LEV is not anticestodal nor it is anti-trematode. LEV has not shown any ovicidal activity such as BZs. Whereas the remedial index of LEV is relatively lower than that of other antinematodal. LEV has also been found effective against hypobiotic larvae of the sheep parasitic nematode, *H. contortus* [1, 4].

The working mode of action of levamisoles has depicted that it works as a cholinergic agonist; it acts as nicotinic acetylcholine receptors on the surface of the nematode muscle cells along with neuromuscular junction. The antinematodal potential of

**Figure 2.**

*Illustration of the mechanism of actions of levamisole and ivermectin against GI parasites.*

LEV is mostly associated with its ganglion stimulant activity. It induces ganglion-like structure in somatic muscle cells of nematodes. The induction ultimately results in determining muscle contractions that are in line with the depolarizing barricades causing paralysis.

The pharmacodynamics of the compound plays an important role in the paralysis that leads to the elimination of helminths promptly through normal intestinal peristalsis (**Figure 2**) [1, 2].
