Mechanisms of Action of Anthelmintics
Anthelmintics must be selectively toxic to the parasite. This is usually achieved either by inhibiting metabolic processes that are vital to the parasite but not vital to or absent in the host, or by inherent pharmacokinetic properties of the compound that cause the parasite to be exposed to higher concentrations of the anthelmintic than are the host cells. While the precise mode of action of many anthelmintics is not fully understood, the sites of action and biochemical mechanisms of many of them 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; this and reproductive processes require proper neuromuscular coordination. Parasites must also maintain homeostasis despite host immune reactions. The pharmacologic basis of the treatment for helminths generally involves interference with the integrity of parasite cells, neuromuscular coordination, or protective mechanisms against host immunity, which lead to starvation, paralysis, and expulsion or digestion of the parasite.
Several classes of anthelmintics impair cell structure, integrity, or metabolism: 1) inhibitors of tubulin polymerization—benzimidazoles and probenzimidazoles (which are metabolized in vivo to active benzimidazoles and thus act in the same manner); 2) uncouplers of oxidative phosphorylation—salicylanilides and substituted phenols; and 3) inhibitors of enzymes in the glycolytic pathway—clorsulon.
The benzimidazoles inhibit tubulin polymerization; it is believed that the other observed effects, including inhibition of cellular transport and energy metabolism, are consequences of the depolymerization of microtubules. Inhibition of these secondary events appears to play an essential role in the lethal effect on worms. Benzimidazoles progressively deplete energy reserves and inhibit excretion of waste products and protective factors from parasite cells; therefore, an important factor in their efficacy is prolongation of contact time between drug and parasite. Cross-resistance can exist among all members of this group, because they act on the same receptor protein, β-tubulin, which is altered in resistant organisms such that none of the benzimidazoles can bind to the receptor with high affinity.
Uncoupling of oxidative phosphorylation processes has been demonstrated for the salicylanilides and substituted phenols, which are mainly fasciolicides. These compounds act as protonophores, allowing hydrogen ions to leak through the inner mitochondrial membrane. 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.
Clorsulon is rapidly absorbed into the bloodstream. When Fasciola hepatica ingest it (in plasma and bound to RBCs), they are killed because glycolysis is inhibited and cellular energy production is disrupted.
Interference with this process may occur by inhibiting the breakdown or by mimicking or enhancing the action of neurotransmitters. The result is paralysis of the parasite. Either spastic or flaccid paralysis of an intestinal helminth allows it to be expelled by the normal peristaltic action of the host. Specific categories include drugs that act via a presynaptic latrophilin receptor (emodepside), various nicotinic acetylcholine receptors (agonists: imidazothiazoles, tetrahydropyrimidines; allosteric modulator: monepantel; antagonist: spiroindoles), glutamate-gated chloride channels (avermectins, milbemycins), GABA-gated chloride channels (piperazine), or via inhibition of acetylcholinesterases (coumaphos, naphthalophos).
Organophosphates inhibit many enzymes, especially acetylcholinesterase, by phosphorylating esterification sites. This phosphorylation blocks cholinergic nerve transmission in the parasite, resulting in spastic paralysis. The susceptibility of cholinesterases by host and parasite varies, as does the susceptibility of these different species to organophosphates.
The imidazothiazoles are nicotinic anthelmintics that act as agonists at nicotinic acetylcholine receptors of nematodes. Their 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. Hexamethonium, a ganglionic blocker, inhibits the action of levamisole.
Monepantel, 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 nicotinic acetylcholine receptors. Binding of monepantel to the receptor results in a constant, uncontrolled flux of ions and finally in a depolarization of muscle cells, leading to irreversible paralysis of the nematodes. These receptors are unique in that they are found only in nematodes.
Derquantel, a semisynthetic member of the spiroindole class of anthelmintics, is an antagonist of B-subtype nicotinic acetylcholine receptors located at the nematode neuromuscular junction; it inhibits 45-pS channels, leading to a flaccid paralysis of nematodes.
Piperazine acts to block neuromuscular transmission in the parasite by hyperpolarizing the nerve membrane, which leads to flaccid paralysis. It also blocks succinate production by the worm. The parasites, paralyzed and depleted of energy, are expelled by peristalsis.
The macrocyclic lactones act by binding to glutamate-gated chloride channel receptors in nematode and arthropod nerve cells. This causes the channel to open, allowing an influx of chloride ions. Different chloride channel subunits may show variable sensitivity to macrocyclic lactones and different sites of expression, which could account for the paralytic effects of macrocyclic lactones on different neuromuscular systems at different concentrations. The 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 paralysis of pharyngeal muscle is more sensitive. As the macrocyclic lactone concentration decreases, motility may be regained, but paralysis of the pharynx and resultant inhibition of feeding may last longer than body muscle paralysis and contribute to worm deaths. None of the macrocyclic lactones are active against cestodes or trematodes, presumably because these parasites do not have a receptor at a glutamate-gated chloride channel. Emodepside acts presynaptically at the neuromuscular junction, where it attaches to a latrophilin-like receptor. This receptor belongs to the group of so-called G-protein coupled receptors. Stimulation of the latrophilin-like receptor by emodepside activates a signal transduction cascade via Gq-protein and phospholipase C, causing an increase in intracellular calcium and diacylglycerol levels. At the end of the signal transduction cascade, vesicles containing inhibitory neuropeptide fuse with presynaptic membranes. After fusion of these membranes, inhibitory neuropeptides may be released into the synaptic cleft to then stimulate a postsynaptic receptor. Recent findings indicate that a second emodepside target is the calcium-activated potassium channel slo-1. Binding to the latrophilin receptor and the slo-1 ion channel leads to inhibition of pharyngeal pumping, paralysis, and death.
The mode of action of praziquantel is not certain, but it rapidly causes tegumental damage and paralytic muscular contraction of cestodes, followed by their death and expulsion.