Let’s hear it for loperamide.
A drug that lets you postpone…
It acts on the plexus of Auerbach,
And decreases smooth muscle tone.
On the face of it, there is not too much explanation required for this one but there is at least one major issues that I would like to cover in this post. In addition there are probably a couple of minor ones as well, so let’s see how it goes.
Loperamide, is a μ-receptor agonist (see opioid terminology) that was first developed in the 1960s by Paul Janssen of Janssen Pharmaceuticals. The impact of opioids on the GI tract is probably as well known as their effect on pain and have certainly been taken for conditions like dysentry since the middle ages1, 2. Indeed, loperamide was preceded at Janssen by two other opioid based anti-diarrhoeals. Trails of loperamide were published in the early 70’s and it was marketed as Imodium, licensed and by the 80’s had become the most prescribed anti-diarrhoeal. In 2013 is was added to the WHO Essential Medicines list proving just how important a medication this is.
Loperamide works by decreasing intestinal transit, slowing the passage of food through the bowel. The GI tract has two types of smooth muscle; circular smooth muscle arranged around the lumen (not unlike arteries and bronchi etc) and longitudinal smooth muscle arranged in strips along the length of the intestine. Between these layers of muscle sits the Plexus of Auerbach3 (or as you are more likely to see it referred to these days: the myenteric plexus), part of the enteric nervous system. This receives inputs from both the sympathetic and parasympathetic branches of the ANS as well as signals from the mucosa and muscle walls. Control of the contraction of these smooth muscle layers is controlled by a complex interaction4 between the ANS, the ENS as well as local mechanical stimuli, such as Bayliss and Starling’s law of intestines. While the exact details about how this is controlled is somewhat sketchy, what at is well known is that acetylcholine and substance P will constrict the gut, while noradrenaline and VIP will dilate the gut. Clearly, given the observations about opioids noted above, μ-receptors (as well as δ- and κ-receptors) are in the mix too. The μ-receptor has been reported on the longitudinal smooth muscle, the but actions of loperamide and endogenous opioids appear not to be direct muscular actions but rather are likely to be pre-synaptic, inhibiting the release of ACh and VIP thus decreasing intestinal motility.
All of which brings us onto the pressing point of why do we get loose stools. Physiologically there are one of two problems here, irrespective of what the specific problem is. These can be broadly described as transit problems or osmotic problems.
Transit issues arise when passage through the gut is too fast to absorb sufficient amounts of fluid (and nutrients); it literally goes straight through you. Osmotic problems are due to a reduction in absorption. This leads to the retention of osmotically active electrolytes in the lumen, which in turn tends to hold fluid there and increase fluid loss5. There is some overlap here, because if absorption is reduced slower transit would allow more time for absorption and so would decrease the osmotic pull. This is why agents like loperamide work, because slowing transit will have an impact whether it is a direct or indirect transit issue.
The larger issue here relates to an old wives’ tale that I have heard a number of times. This is that you should not take anti-diarrhoeals as the loose stool is the body trying to clear the infection. Now, fair enough there are some cases where impeding the loss of infectious agents is not good and loperamide would be contraindicated. For example potential invading bacteria such as E. coli 0157 or Salmonella but also C. difficile where failure to clear is an issue. However, as appropriate as it is to clear these, that is not the cause of the diarrhoea. Just the use of the word “try” should make you uneasy as this is another example of a teleological argument, basing an action on its consequence rather than its stimuli.
In most cases infective diarrhoea arises from disruption of the mechanisms mentioned above. Norovirus, for example, appears to damage the microvilli on the epithelial cells and lead to hyperplasia of the crypt cells. The impact of this would be to decrease absorption and increase secretion, leading to an osmotic diarrhoea. It is not dissimilar for many bacterial infections, both E. coli and V. cholerae release endotoxins that lead to the hypersecretion of Cl– from the crypt cells, again producing an osmotic diarrhoea while other infections or inflammation simply decrease the surface area for absorption. In these cases, slowing transit allows for more time to absorb water and solutes and so less watery stools and subsequently less dehydration. Since dehydration is the main factor in leading to diarrhoeal-related death6, this is why it is an essential medication.
1. There is an excellent review of the μ-receptor pharmacology here. In case your interested my favourite opioid receptor is the ORL1. If you are going to be pedantic and insist upon a classical opioid receptor then it’s the κ-receptor.
2. Apparently there is an old saying amongst pain specialists: ‘God gave them two hands so that while one hand prescribes an opioid, the other will prescribe a laxative’. I cannot comment on that myself but this paper by Bril et al., thought it worthy of mention.
3. Some people are not keen on eponymous names. They point to inconsistencies in whether the name reflects the true discoverer, ethical concerns about the practices and motives of some and then there is the simple practical concern that these are not at all descriptive. The Plexus of Auerbach and its near neighbour, Meissner’s Plexus are perhaps better described as the myenteric plexus and the submucosal plexus. Personally I do not agree and I happen to prefer eponymous names, mainly because the term myelin sheath gaps as an alternative for the wonderful Nodes of Ranvier is just mind-numbingly awful.
4. To give some idea about how complex, I have a four year old (2014) GI textbook which simply states the exact pathways are being elucidated.
5. This is how osmotic laxatives such as polyethylene glycol work.
6. WHO estimates more than 500,000 infant deaths per year from diarrhoeal disease making it the second largest cause of death in infants