Mechanisms of action in antiparasitic drugs
Antiparasitic drugs are vital in combating diseases caused by parasites, which can lead to significant health issues, particularly in tropical developing countries. These drugs work through various mechanisms to inhibit the growth and reproduction of pathogenic parasites, classified mainly as protozoa, helminths, and ectoparasites. Key mechanisms include the inhibition of the neuromuscular and neuronal systems, leading to paralysis of the parasite, and the disruption of energy metabolism that hinders the parasite's ability to thrive. Additionally, some drugs damage the integrity of the parasite's cellular membranes, causing further dysfunction. Other mechanisms target the reproductive processes of parasites, effectively preventing their lifecycle from continuing. The rising prevalence of parasitic infections, exacerbated by factors such as increased travel and immunosuppressive treatments, highlights the ongoing need for effective antiparasitic agents and further research into new treatments.
Mechanisms of action in antiparasitic drugs
Definition
Antiparasitic drugs, or antiparasitics, are used to prevent parasites (harmful organisms) from multiplying in and colonizing the human body.
Parasites and Parasitic Diseases
Parasites are organisms that live at the expense of another organism, or host. Pathogenic parasites cause diseases such as malaria, trypanosomiasis (sleeping sickness), leishmaniasis, schistosomiasis, and filariasis, all of which affect millions of people around the world each year. These diseases are a significant public health problem in tropical developing countries and lead to blindness, impaired physical and intellectual development, organ failure, disfiguration, and death. Children are especially at risk in endemic areas.
Most pathogenic parasites fit into one of the following three categories: protozoa, helminths, and ectoparasites. Protozoa are single-celled organisms that replicate rapidly in the infected host, often in the gastrointestinal tract. Helminths are complex multicellular organisms such as tapeworms, roundworms, and flukes. Ectoparasites live on the outer surface of the body and include lice, scabies, and ticks.
Disease Control
Local and international efforts to control parasitic diseases have had some success by educating people about the spread of parasites. In addition, vaccine and vector control have had beneficial effects. However, effective drugs against these pathogens remain essential to reduce the burden of these diseases. Antiparasitic agents act through a variety of different mechanisms, including inhibition of the neuromuscular system, inhibition of the neuronal system, inhibition of energy metabolism, damage of the membrane, and interference with reproduction.
Inhibition of the neuromuscular system. Inhibiting the neuromuscular system of a parasite results in paralysis, which enables the host body to expel it naturally. This inhibition can be achieved by blocking the transmission of nerve impulses to the muscle fiber at the neuromuscular junction. Drugs that are competitive neuromuscular blockers (such as piperazine) prevent the binding of the neurotransmitter acetylcholine to its cognate receptors. In contrast, depolarizing neuromuscular blockers (levamisole, pyrantel, and morantel) bind to and activate the acetylcholine receptors, but the depolarizing effect on the muscle fiber is prolonged because the drugs are not degraded quickly. In that way, the muscle fiber becomes unresponsive to normal nerve signals. Cholinesterase inhibitors, such as dichlorvos and trichlorfon, achieve a similar effect by blocking the action of enzymes that degrade acetylcholine.
Inhibition of the neuronal system. Paralysis of the parasite can also be induced by activating G-protein-coupled receptors at the neuromuscular junction (with a drug such as emodepside), which stimulates the release of neuropeptides that impair muscle function. Macrocyclic lactones, such as avermectins and milbemycins, act on nerve cells by binding to gated chloride channels, thereby increasing cell permeability and hyperpolarization. These compounds paralyze the pharyngeal pumping mechanism of helminths and appear to prevent the secretion of proteins needed to evade the host immune system.
Inhibition of energy metabolism. Benzimidazoles (such as thiabendazole, mebendazole, and albendazole) act against helminths and some protozoa by binding to beta-tubulin; this prevents the formation of microtubules, which are needed for the cellular uptake of glucose. In addition, benzimidazoles appear to inhibit fumarate reductase (an enzyme important in anaerobic respiration) and to degrade the endoplasmic reticulum and mitochondria, which reduces the production of adenosine triphosphate needed for energy transfer.
The drugs clorsulon, sodium stibogluconate, and meglumine antimoniate inhibit glycolysis, and nitazoxanide inhibits electron transfer by blocking pyruvate-ferredoxin oxidoreductase, an enzyme unique to parasites. Atovaquone is a ubiquinone analog that appears to inhibit electron transport in mitochondria through an interaction with cytochrome B, and niclosamide targets the mitochondria by inhibiting oxidative phosphorylation. Primaquine also appears to disrupt mitochondrial function, although the precise mechanism of action is not clear.
Damaging membrane integrity. Damaging the cellular membrane of muscle cells results in calcium release from intracellular stores. Praziquantel and epsiprantel are two drugs that produce this effect in helminths, thereby causing paralysis and stimulating muscular contractions. The drugs also disrupt the parasite’s surface membrane to expose antigens, which are then recognized by the host immune system.
Interfering with reproduction. Several drugs target the reproductive cycle of parasites. The inhibitory effect of benzimidazoles against microtubule formation is also responsible for their ovicidal and larvicidal effects. The drug fumagillin inhibits the proliferation of microsporidia, possibly by blocking the action of methionine aminopeptidase 2, an enzyme involved in protein translation. One of the actions of macrocyclic lactones, which bind to ion channels in nerve and muscle cells, is to paralyze the reproductive tract in adult female helminths.
Antiparasitic drugs may also be broken down into categories that divide common drugs by the parasites they target. Antiprotozoal agents treat protozoa infections, including the parasites that cause malaria. Antihelminthic agents treat infections caused by the various kinds of parasitic worms. Ectoparasiticides are used to kill lice and scabies. Many antiparasitic medications are only effective against a small range of parasites.
Impact
Parasitic infections are a significant health burden for many of the world’s poorest people. These diseases are on the rise because of the use of immunosuppressive drugs, because of immigration, and because of increased travel to affected regions. Many parasitic infections cannot be treated with the drugs that are now available, so further research and development is warranted, and necessary.
Bibliography
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Moore, Thomas. “Agents Active Against Parasites and Pneumocystis.” In Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, edited by Gerald L. Mandell, John E. Bennett, and Raphael Dolin. 7th ed. New York: Churchill Livingstone/Elsevier, 2010.
Pearson, Richard. “Antiparasitic Therapy.” In Cecil Medicine, edited by Lee Goldman and Dennis Arthur Ausiello. 23d ed. Philadelphia: Saunders/Elsevier, 2008.