Sunday, March 3, 2013

Keeping the Worms at Bay: Mechanisms Behind Antihelminthic Agents

Lately I've been reading a lot about immunity and drug-parasite interactions.  So, I thought it was time to share some of that knowledge with all of you!  Today, we will talk about a few antihelminthic drugs (a.k.a. "de-wormers") and how these drugs work to rid parasite hosts of their wormy burdens.

First of all, antihelmenthics typically work by either stunning worms (vermiguges) or by killing them altogether (vermicides).  There are a number of natural remedies for riding oneself of parasitic worms.  Most involve plants that are able to affect the worms when ingested directly, when made into a teas, or when inhaled.  The validity of most of these remedies are questionable, but there are some that have been scientifically proven to be effective antihelminthic agents (such as creosote, tobacco, and wormwood).  In fact, some of these natural compounds for the basis for pharmaceuticals.  Then again, others are products of folk medicines which have yet to be tested in scientific laboratories.  These include treatments with cloves, garlic, chive juice, black walnut, pineapples, honey mixed with vinegar, plumeria, and even diatomaceous earth (which originates from diatoms rather than plants).

For this post, we will focus more specifically on the pharmaceutical antihelminthics.  These drugs have been developed to treat flatworms, such as flukes and tapeworms, as well as roundworms, such as hookworms, threadworms, and maw worms.  Flukes are often treated using antimonials, metrifonate, oxamnaquine, praziquantel, or closantel.  Tapeworms are treated using niclosamide, benzimidazoles, or praziquantel.  Roundworms  that infect the intestine may be treated using piperazine, benzimidazoles, morantel, pyrantel, levamisole, avermectins, closantel, or emodepside.  Tissue-invading roundworms tend to be treated using diethylcarbmazine, surmin, or ivermectin.

Now that I've scared some of you with all these big, difficult to pronounce words, let's try to simplify things by looking at the most commonly used drugs and how they work to cleanse hosts of their parasites.

These drugs include a variety of broad spectrum antihelminthics.  The first drug of this class was discovered in 1961 and was called "thiabendazole".  The drugs belonging to this class all work by compromising functionality of the worms' cytoskeletons.  This makes it difficult for the worms to move and to reproduce.  Although these compounds are highly effective for most types of roundworms and some tapeworms, there are some species which have developed a resistance to these drugs.  The resistance has been attributed to the replacement of a single amino acid with a different amino acid within the alleles controlling β-tubulin within the cytoskeletons of these worms that renders the drugs useless.  Drugs in this class include Albendazole (treats threadworms, whipworms, other roundworms, and tapeworms), Mebendazole (treats pinworms, hookworms, and other roundworms), Thiabendazole (treats hookworms and other roundworms), and Triclabendazole (treats liver flukes).

This drug was first introduced as an antihelminthic in the 1980s.  It is a derivative of avermectin, which comes from Streptomyces avermitilis, a  type of bacterium.  (Members of the genus Streptomyces have also been used to create antifungal, antibacterial, and even anticancer drugs.)  This drug interacts with a variety of ion-gated channels, but is specifically good at interfering with glutamate-gated chloride channels within the bodies of nematodes.  The drug utilizes these channels via overactivation to cause paralysis of musculature in both the body wall and in the pharynx (not all species of worms are subjected to pharyengeal paralysis).  Mutations in glutamate-gated chloride channels can lead to resistance, but requires multiple mutations rather than singular mutations.  This makes resistance much more complicated and as a result, less frequently found in nature.


This drug is especially good for killing tapeworms.  In fact, it's often classified as a teniacide (from the word "tenia" which refers to tapeworms).  It isn't really effective against roundworms even to a small degree, but tapeworms exposed to this drug are killed on contact.  This happens because the drug has the ability to "uncouple oxidative phosphorylation"...which translates to, the drug stops all energy production (ATP synthesis) within the worm's cells.  Essentially, it starves the worms on a cellular level.

Nicotinic Receptor Antagonists
This drug class includes drugs like levamisole, pyrantel, and morantel.  All of them act as antagonists at nicotinic receptors within muscles.  They cause continual muscle spasms that eventually lead to paralysis.  This happens because nicotinic acetylcholine receptors will shut down communication when they have been excited for too long.

This drug was first used in the 1950s to treat threadworm infections in children.  It is still used for many over the counter types of medicines.  It works by causing a paralysis within the muscles lining the body wall of these worms.  This is achieved by mimicking the neurotransmitter GABA to induce the relaxation of these muscles.  Diethylcarbmazine is a synthetic derivative of piperazine that is helpful for the treatment of tissue-dwelling roundworms in humans and for the prevention of heartworms in dogs.

Created in German laboratories in the 1970s, this drug has become an important means for controlling flatworm infections.  It works, and it works really well.  Unfortunately, no one is really sure exactly how it works.  Through experimentation with blood flukes, it seems that the drug increases permeability of cell membranes and induces an influx of calcium ions leading to sustained contractions.  This leads to paralysis of the parasites, which causes them to become dislodged from their hosts and leaves them floating in bodily fluids where they are either destroyed by immune reactions or filtered out into waste materials.  Other studies hypothesize that this drug stops the worms' ability to synthesize purines, such as adenosine, making them vulnerable to host digestion.

Moral of the Story
There is certainly more than one way to kill a parasitic worm...sustained contractions, cellular starvation, deprivation of vital nucleotides...but in the end, we are just happy that these antihelminthics work.  As with all drugs, we have to be weary of over-prescription to prevent drug resistance, but it is still comforting to know not just that these drugs work, but how they work, and why they work so well.  Antihelminthics, we salute you and all of your devastatingly intricate modes of action leading to what are probably pretty painful deaths for our parasites!

A person dispensing ivermectin tablets to a young girl during a central point distribution in her village.

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