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Pharmacodynamics: Mechanisms of Anthelmintic Action in Animals

ByEdwin Claerebout, DVM, PhD, DEVPC, Laboratory of Parasitology, Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, Belgium;
Carlos E. Lanusse, Tandil University
Reviewed/Revised Apr 2025

Anthelmintic drugs must be selectively toxic to the parasite, typically either by inhibiting biochemical processes that are vital to the parasite (but absent in or not vital to the host) or by interfering with the parasite's correct neuromuscular coordination. The potency of most anthelmintics depends on their affinity for a specific receptor but also on the kinetic properties that facilitate achievement of effective drug concentrations at the site of action.

A strong relation exists between pharmacokinetics (which determine drug exposure at the parasite location site) and pharmacodynamics (drug effect based on a specific mode of action). Thus, understanding the pharmacokinetic-pharmacodynamic relationship for the most common drugs is critical to optimizing their use to control helminth parasites. While the precise mode of action of many anthelmintics is not fully understood, their sites of action and biochemical mechanisms are generally known.

Parasitic helminths must maintain an appropriate feeding site, and nematodes and trematodes must actively ingest and move food through their digestive tracts to maintain an appropriate energy state; digestive and reproductive processes require proper neuromuscular coordination. Parasites must also maintain homeostasis despite host immune reactions. The pharmacodynamic basis of anthelmintic activity generally involves interference with the integrity of parasite cells, neuromuscular coordination, or protective mechanisms against host immunity that lead to starvation, paralysis, death, and expulsion or digestion of target parasites.

Cellular Integrity in Pharmacodynamics of Anthelmintics in Animals

Several classes of anthelmintics impair cell structure, integrity, or metabolism:

  • inhibitors of tubulin polymerization: benzimidazoles and pro-benzimidazoles (which are metabolized in vivo to active benzimidazoles and thus act in the same manner)

  • disrupters of parasite tegument

  • uncouplers of oxidative phosphorylation: salicylanilides and substituted phenols

  • inhibitors of enzymes in the glycolytic pathway: clorsulon

Microtubules are hollow tubular organelles that exist in a dynamic equilibrium with tubulin, the microtubule subunit.

Tubulin exists as a dimeric protein comprised of alpha and beta subunits. Benzimidazole pharmacological activity is based on binding to parasite beta tubulin, which produces subsequent disruption of the tubulin-microtubule dynamic equilibrium (see figure Levamisole and albendazole comparison). Thus, all the functions ascribed to microtubules at the cellular level (ie, cell division, maintenance of cell shape, cell motility, cell secretion, nutrient absorption, and intracellular transport) are altered.

Microtubules are found in animal, plant, and fungus cells. However, the rate constant for benzimidazole dissociation from parasite tubulin is much lower than the rate constant for dissociation from mammalian tubulin. These differences in dissociation rates between benzimidazole and tubulin in host and parasites may explain the selective toxicity of benzimidazole compounds to parasites and their wide safety margin in the mammalian host.

The primary mechanism of action of benzimidazoles is microtubule disruption within the parasite. Enzymatic inhibition of the acetylcholinesterase and various metabolic cascades have also been associated with benzimidazole activity on nematodes.

Carbohydrate and energy metabolism in helminth parasites differs from that of the mammalian host. Also, parasites exhibit a wide variation in their carbohydrate breakdown pathways during their life cycle. Many parasites shift their metabolism between predominantly aerobic and predominantly anaerobic according to their life stage, and that shift can alter their anthelmintic susceptibility. Energy metabolism in the adult stages of the liver fluke, Fasciola hepatica, is almost completely anaerobic, and aerobic processes remain only in the parasite's tegument; this is also one of the main absorptive surfaces for drug uptake by the fluke and may be a primary target for anthelmintic action.

Studies in F hepatica have shown that the transtegumental transfer mechanism is critical to achieve sufficient drug concentration at the site of action and exert the drug's flukicidal action. Disruption of the tegument by different mechanisms (including those involved in energy generation) can have severe consequences for the parasite because the drug can penetrate deeper and disrupt subtegumental tissues. Surface damage may also be exacerbated by bile's surfactant action.

Uncoupling of oxidative phosphorylation processes has been demonstrated for the salicylanilides and substituted phenols, which are mainly fasciolicides. Although isolated nematode mitochondria are susceptible, many fasciolicides are ineffective against nematodes in vivo, apparently due to a lack of drug uptake. Exceptions are the hematophagous nematodes, eg, Haemonchus and Bunostomum. Closantel and other salicylanilides are uncouplers of the oxidative phosphorylation in the liver fluke, Fasciola hepatica.

Niclosamide is highly effective against most tapeworm species in companion animals, although it has poor efficacy against Dipylidium spp and Echinococcus granulosus. In ruminants, the drug is also effective in treating common tapeworms, such as Moniezia spp and Thysanosoma spp. In horses, niclosamide may be used to treat Anoplocephala spp.

Niclosamide´s taeniacidal activity involves interference with glucose absorption, inhibition of oxidative phosphorylation, and stimulation of ATP activity at the mitochondrial level. All these mechanisms lead to the parasite's death and subsequent digestion within the gut.

Salicylanilides disrupt the mitochondrial membrane gradient by which ATP is generated, whereas clorsulon is a competitive inhibitor of glycolysis. As a result, both anthelmintics kill parasites by interrupting critical metabolic pathways.

Neuromuscular Coordination in Pharmacodynamics of Anthelmintics in Animals

Interference with neuromuscular coordination in parasites can occur by inhibiting the breakdown of neurotransmitters or by mimicking or enhancing their action. The result is paralysis of the parasite. Either spastic or flaccid paralysis of an intestinal helminth allows it to be expelled by the host's normal peristaltic action. Several categories of anthelmintics function in this way:

  • drugs that act via a presynaptic latrophilin receptor (emodepside)

  • various nicotinic acetylcholine receptors (agonists: imidazothiazoles, tetrahydropyrimidines; allosteric modulator: monepantel; antagonists: spiroindoles)

  • glutamate-gated chloride channels (avermectins, milbemycins)

  • gamma-aminobutyric acid (GABA)-gated chloride channels (piperazine)

The imidazothiazoles are nicotinic anthelmintics that act as agonists at nicotinic acetylcholine receptors (nAChRs) of nematodes (see figure Levamisole and albendazole comparison). Imidazothiazoles' anthelmintic activity is mainly attributed to their ganglion-stimulant (cholinomimetic) activity, whereby they stimulate ganglion-like structures in somatic muscle cells of nematodes. This stimulation first results in sustained muscle contractions, followed by a neuromuscular depolarizing blockade resulting in paralysis.

Levamisole, a synthetic imidazothiazole, is a cholinergic receptor agonist and elicits spastic muscle paralysis due to prolonged activation of the excitatory nAChRs on nematode body wall muscle. Pharmacological analysis has provided evidence for subtypes of nAChR: an N-subtype (preferentially activated by nicotine and oxantel), a B-subtype (preferentially activated by bephenium), and an L-subtype (preferentially activated by levamisole and associated with levamisole resistance). Its uptake in helminth parasites is considered to be mainly by a transcuticular mechanism.

Tetrahydropyrimidine compounds (pyrantel, oxantel, morantel) are highly potent cholinergic agonists. These anthelmintics cause paralysis by virtue of their effect at nicotinic receptors. 

Monepantel, as the only commercially available amino-acetonitrile derivative, is a direct agonist of the mptl-1 channel, which is a homomeric channel belonging to the deg-3 family of nAChR. Binding monepantel to the receptor results in constant uncontrolled ion flux and, finally, in muscle cell depolarization, leading to irreversible paralysis of the nematodes. These receptors are unique in that they only occur in nematodes.

Spiroindoles act as antagonists of neuronal nicotinic cholinergic receptors in both nematodes (flaccid paralysis in vitro) and mammals, and this mechanism appears to underlie both their efficacy and their toxicity. The spiroindole compound 2-desoxoparaherquamide, known as derquantel, is a semisynthetic derivative that shows low affinity for mammalian receptors and is active against both benzimidazole- and ivermectin-resistant Haemonchus contortus. Derquantel is an antagonist of B-subtype nAChR, located at the nematode neuromuscular junction by inhibiting 45-pS channels, leading to a flaccid paralysis of nematodes.

Piperazine blocks transmission by hyperpolarizing nerve membranes at the neuromuscular junction, leading to parasite immobilization by flaccid paralysis, consequent removal from the predilection site, and death.

Macrocyclic lactones act by binding to glutamate-gated chloride channel receptors in nematode and arthropod nerve cells (see figure Macrocyclic lactones: mechanisms of action). This causes the channel to open, allowing an influx of chloride ions. Different chloride channel subunits can show variable sensitivity to macrocyclic lactones and different sites of expression, which could account for their paralytic effects on different neuromuscular systems at different concentrations.

Macrocyclic lactones paralyze the pharynx, the body wall, and the uterine muscles of nematodes. Paralysis (flaccid) of body wall muscle may be critical for rapid expulsion, even though pharyngeal muscle is more sensitive to paralysis. As macrocyclic lactone concentration decreases, motility may be regained; however, pharyngeal paralysis and resultant inhibition of feeding may endure longer than body muscle paralysis and contribute to worm death.

Macrocyclic lactones are not active against cestodes or trematodes, presumably because these parasites do not have a receptor at a glutamate-gated chloride channel.

Emodepside represents a relatively new class of anthelmintics, with a novel mechanism of action that renders it fully effective against nematodes resistant to other drug classes. By binding to a latrophilin-like receptor and an ion channel known as slo-1, emodepside inhibits pharyngeal pumping in the nematode and ultimately causes paralysis and death. 

Cestode infections are best treated with praziquantel. The mechanism of action is related to calcium-channel disruption. Paralysis results, leading to tapeworm death.

The primary effect of praziquantel is the contraction of parasite musculature, which is followed by a rapid vacuolization of the syncytial tegument. Muscular contraction and tegumental disruption are followed by exposure of parasite antigens, binding, and penetration of host immune cells into the parasite. Metabolic changes include lactate release and decreases in glucose uptake, glycogen storage, and ATP content. All these effects are attributed either directly or indirectly to an alteration of intracellular Ca2+ homeostasis.

Praziquantel effects are thought to be mediated by the release of intracellular stored Ca2+, in addition to the increase of Ca2+ influx across the tegument.

Key Points

  • Anthelmintic drugs disrupt cellular integrity, metabolism, or neuromuscular function in the parasite, leading to death.

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