Mechanisms of Action of Active Ingredients

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 characteristic pharmacokinetic properties of the compound that cause the parasite to be exposed to higher concentrations of the anthelmintic than the host cells. While the detailed mode of action of many anthelmintics is not fully understood, the sites of action and biochemical mechanisms of many of them are mostly 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.

Therefore, the pharmacologic basis of the treatment for helminths generally involves interference with:

• The integrity of parasite cells.
• Neuromuscular coordination.
• 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, such as benzimidazoles (and pro benzimidazoles, which are metabolized in vivo to active benzimidazoles and thus act in the same manner).

Microtubules (MTs) are essential players in the function of the cell as they are responsible for many cellular processes, including cell division (mitosis). Microtubules are found in the cytoplasm of almost all eukaryotic cells and they elongate by tubulin polymerization. Microtubules are hollow fibres which serve as a skeletal system for living cells that allow them to undergo mitosis or to regulate intracellular transport.

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 the excretion of waste products and protective factors from parasite cells; therefore, an important factor in their efficacy is a prolongation of contact time between the drug and the 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.

2.  Uncouplers of oxidative phosphorylation, such as salicylanilides and substituted phenols.

Oxidative phosphorylation is the primary purpose of oxygen respiration (the exchange of oxygen and carbon dioxide) and the principal use of breathed-in oxygen to generate energy (in the form of ATP) in the body.

Uncoupling of oxidative phosphorylation processes has been demonstrated for the salicylanilides and substituted phenols, which are mainly fasciolicides (anthelmintics against Fascioloides spp.). These compounds act as protonophores (compounds capable of electrogenic transport of protons across membranes), allowing hydrogen ions to leak through the inner mitochondrial membrane. The mode of action is not exactly known, but in blood-sucking parasites (hairworm and liver fluke) the oxidative phosphorylation in mitochondria is stopped. The synthesis of ATP is prevented by interfering with the mitochondria’s permeability. Because of this interference, the parasite does not have enough energy for essential processes. Liver flukes display paralysis, they stop eating and they lose their position in the bile ducts of the host animal.

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 (or blood-sucking) nematodes, e.g., Haemonchus and Bunostomum.

Overdose with salicylanilides can cause the animal to become blind

Tapeworms cannot absorb glucose. Because of the action of niclosamide, the cessation of the oxidative phosphorylation process occurs in the mitochondria in the cells of tapeworms. The Krebs cycle is blocked and lactic acid builds up, causing the parasite to die. The dead tapeworms are digested as they are excreted from the host animal’s body.

3.  Inhibitors of enzymes in the glycolytic pathway, such as clorsulon.

Similar to oxidative phosphorylation, the glycolytic pathway is important for the production of energy (ATP) in cells which is essential for cellular function. Without glycolysis, cells fail to survive.

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. Neurotransmitters are chemical messengers that the body cannot function without. They carry chemical signals (“messages”) from one neuron (nerve cell) to the next target cell. The next target cell can be another nerve cell, a muscle cell or a gland.

The result of inhibiting or enhancing neurotransmitters in the body of the parasite is the paralysis of the parasite. Either spastic (such as organophosphates, imidazothiazoles, AADs, praziquantel) or flaccid (such as macrocyclic lactones, piperazine, spiroindoles) 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.
• Various nicotinic acetylcholine receptors (imidazothiazoles, AADs, spiroindoles).
• Glutamate-gated chloride channels (macrocyclic lactones).
• GABA-gated chloride channels (piperazine).
• The inhibition of acetylcholinesterases (organophosphates).

Parasite Resistance:

Although it may be thought that chemotherapeutic control of parasite infections is currently satisfactory, selection for parasite resistance is an increasing concern. As the effectivity of agents gradually decreases internal and external parasites thus survive more easily.

Resistance is the development of the ability of a strain of insects to tolerate doses of toxicants which would prove lethal to the majority of individuals in a normal population of the same species.

One important factor that contributes to parasitic resistance is the repeated use of the same active ingredient year after year to control the parasite of concern. For example, hen the same drug or active ingredient is used continuously, all the ticks that are susceptible to the drug are eradicated, while the resistant ticks systematically increase. As a result, the entire tick population on the farm can become completely resistant to the active ingredient in the medicine.

The misuse of antiparasitic agents by farmers also contributes to parasite resistance. If the parasite of concern is exposed to lower concentrations of the antiparasitic agents over some time, or if the antiparasitic product is not applied in the correct dose, the parasite of concern will develop resistance to the agent or active ingredient. The misuse of antiparasitic agents, in particular, contributes to the development of parasite resistance.

In addition, many farmers “formulate” antiparasitic remedies themselves. Besides being illegal, the parasite is exposed to low concentrations of the active ingredient and this causes resistance. Nor can it be said with any certainty that the active ingredient is not absorbed into the tissues of animals and is, therefore, a danger for human consumption.