This chapter is relevant to Section O2(i) from the 2017 CICM Primary Syllabus, which expects the exam candidate to "Describe the pharmacology of aperients, laxatives and other drugs that affect gastrointestinal motility". The CICM curriculum designers have tagged this subject with an L1 level of importance, which suggests we should know it in detail. This is counterfactual, as this topic has never appeared in the written exam, and so could not possibly be a priority for anybody. Well, no, to be fair, 30% of an ammonia question was related to lactulose, but really this is hardly any representation. What follows is an attempt to reconcile the daily clinical importance of the material with the need to focus on exam essentials.
What could they possibly ask about these drugs in a foundational critical care exam? Certainly practical uses and applications would be left for later stages of training (eg. where the management of constipation in ICU or prokinetic agents and feed intolerance are discussed). Probably nothing about the ADME either, as most of these drugs really do not have any curious pharmacokinetic properties. The most likely question on this topic would probably be something about classifying laxatives and comparing their mechanisms of action and side effects. Thus:
Drug class examples Mechanism Adverse effects Bulk-forming laxatives
Large polymers which trap water in a gel matrix, increasing the mass and water content of stool and thus encouraging peristalsis
- Abdominal distension
- Bowel obstruction
- Delayed absorption of nutrients
- Delayed absorption of drugs
- Ionic salts (magnesium)
- Saccharides, eg. lactulose
- Sugar alcohols, eg. mannitol
- Magcogols, eg. polyethylene glycol
Create an osmotic gradient which counteracts the absorption of water in the colon, thereby increasing the water content of stool
- Abdominal distension
- Electrolyte depletion
- Volume depletion
- Mineral oil
Emulsify the stool and make it more slippery, thereby decreasing the resistance to its passage
- Decreased absorption of fat-soluble vitamins
- Pruritis Ani
- Lipid pneumonitis
- Rectal seepage
Surfactant effect: increase the access of water to stool particles, increasing its water content and decreasing its viscosity
- Increased absorption of lipids and lipid-soluble molecules (eg. alkanes)
- Increased (more rapid) absorption of fat-soluble drugs
- Diphenylmethane derivatives (eg. bisacodyl,sodium picosulfate, phenolphthalein)
- Ricinoleic acid
- Anthraquinones (eg. senna)
Increase peristalsis and gut secretory activity by a number of mechanism, including PGE2- mediated increase in chloride secretion and inhibition of enterocyte Na+/K+ ATPase
- Pseudomelanosis coli
- "Cathartic colon"
- Enteric neuropathy
Increase the colonic chloride secretion, whether by increasing cGMP or by directly activating chloride channels, which leads to a net loss of water through the bowel
- Volume depletion
- Theoretically, metabolic alkalosis
Increase gut motility by stimulatinfg the myenteric plexus, where 5-HT is a major excitatory neurotransmitter
- Ischaemic colitis (tegaserod)
- Cardiac ischaemia (tegaserod)
- QTc prolongation (cisapride)
Act as motilin receptor agonists, which stimulates contraction by activation of smooth muscle L-type calcium channels, producing increased antral activity, increased gastric emptying, and more high-amplitude propulsive contractions
- QT interval prolongation
- Potential antimicrobial resistance
- Increased risk of C. difficile infection
By acting directly or indirectly at muscarinic receptors in the gut, increase the availability of intracellular calcium and increase the contractility of the intestinal smooth muscle
- Increased bronchial secretions
Reverse peripheral effects of opioids on the gut by direct antagonist activity against intestinal δ- and κ-opioid receptors
- Theoretically, counter-analgesic effects with systemic absorption
- May produce peripheral features of opioid withdrawal
This unglamorous topic does not attract a lot of detailed literature attention. The best you can expect, from a single article, is some broad brushstrokes outlining the major classes and their most interesting properties. Of the articles that do this, Xing & Soffer (2001) is probably the best-referenced. Avila (2004) and Schiller (1999) are also reasonably detailed, in the sense that too much detail would be unreasonable.
This area of pharmacology is for some reason infested with an abundance of euphemistic terms. Through the literature, one finds sanitising terms like "aperients", "laxatives", "purgatives" and "evacuants" being used to distract from the fact that these are drugs designed to generate an overabundance of liquid faeces.
Whatever the purpose of this nomenclature might be, it is certainly not to increase clarity. For example, the meaning and origin of the term "prokinetics" seems easy enough to grasp intuitively, but what exactly is the difference between aperients and laxatives? Etymology is of no help here (because when is it ever); "aperient" is an archaic term used probably since the 1600s, a derivative of the Latin aperire, "to open" (the same root as aperture), whereas "laxative" comes from laxare, "to loosen". The exact choice of words probably does not matter, as opening or loosening the bowel is certainly not how these drugs work. Popular online dictionaries and complementary medicine propaganda seem to make some sort of distinction between them, suggesting that aperients are "mild laxatives", but a lot of professional literature does not seem to support this, suggesting that the terms are interchangeable. It's a question that the reader should regard as unimportant. The rest of this chapter uses "laxative" purely because the letter "x" in its name increases its objective coolness by 75%.
Whatever you call them, fortunately at least the subclasses of this group seem to be divided on some sort of vaguely objective basis, even though the exact names of each class might vary from textbook to textbook:
These classifications seem to enjoy a wide acceptance, and replace older terminology, which had a somewhat more dramatic character. To quote from "The Therapy of Dropsy" by Marvin (1940):
"The classical division of aperients is into - Laxatives, which increase the bulk of the stools but do not alter their consistency; purgatives, which produce unformed motions; hydragogues, which are followed by watery stools; drastic purgatives, which excite an inflammatory reaction in the intestine..."
There would probably be no practical benefit from a detailed exploration of each member of each class. Broad class-based generalisations will be discussed in the short summary which follows, with digressions on pharmacological properties taken only where the tangent seems valuable.
This group is difficult to define very precisely. Most authors mention that they increase the mass or volume of stool, which means that theoretically small metal spheres could be described as "bulk-forming". A better class definition would probably incorporate their main mechanism of action, which is to accumulate bowel water and make it inaccessible for reabsorption, thereby increasing the water content of stool.
Often described as "gentle" or "natural", bulk-forming laxatives are usually derived from some undigestable plant carbohydrate, and are usually long starch molecules. There are two main variants on this theme: branching molecules which end up being arranged randomly (producing a non-viscous colloid solution) and linear polymers which either arrange themselves regularly or which cross-link between adjacent fibres. The latter variety form water-trapping gels, often referred to as mucilage, as if this topic did not have enough weird gross terminology.
Of the most common ones:
Of these, all have basically the same properties, and similar side-effects:
The mechanism of action of all these substances is basically the same, uniting them as a class. By ensuring that water remains in the stool, they increase the volume of intestinal content, thereby producing an increased distension of the intestinal walls. This stretch is a peristaltic stimulus, which then promotes gut motility. Following from this, one might rightly expect these drugs to lose their effectiveness in scenarios where intestinal water is lacking (eg. patients with stomach emptying), or where the intestine is not inclined to respond to normal signals (eg. where it is infected, bruised or ischaemic). In short, these may not be the best choice in the critically ill patient.
This group functions very much like bulk-forming laxatives, in the sense that all of these agents increase the water content and volume of stool. Like the bulk-forming laxatives, the osmotic group is characterised by being molecules resistant to absorption in the gut. Unlike the long and branching starchy molecules of the bulk-forming group, osmotic laxatives tend to be small molecules, and instead of trapping water in some kind of viscosity-enhancing hydrogel, they prevent its absorption by increasing the osmolality of intestinal content. One might expect there to be a lot of overlap between these groups, as psyllium and friends all also have an osmotic effect, but because those arabinose/xylose polymers have a molecular weight of about 1500 kDa, their concentration in the gut is usually measured in picomoles per litre (one mole = 1500 kg). In contrast, the molar mass of lactulose is 342g/mol, which means one's daily dose might be up to 500mmol - an osmotically relevant amount, considering all of those molecules plan to stay in the gut lumen.
Following from this, one might expect any molecule which is not absorbed in the gut to act as an osmotic laxative, and this is actually broadly very true. Basic nutrients can function as osmotic laxatives if the absorptive capacity of the gut is decreased (eg. norovirus) and this effect is a common cause of diarrhoea in the ICU, where osmotically active NG feeds are administered into damaged intestinal tracts. However there are several classes of molecule which we use as intentional osmotic laxatives, which are:
The word "macrogol" is used to refer to the range of different polyethylene glycols which are commercially available. Just this one manufacturer seems to be selling different versions ranging from 400 Da to 8,000 Da. The macrogols in common medical use for bowel lavage seem to be composed of mainly PEG-3350, i.e. with a molecular mass of 3,350 g/mol. Apparently the cut-off is about 1500 Da; anything more than that is not absorbed, and therefore has a chance to make its mark on the colon.
Irrigating your gastrointestinal tract with hundreds of mmols of something unabsorbable cannot be without its consequences. The undesirable effects of these drugs are:
Occasionally referred to as "emollient" laxatives, these substances exert a purely mechanical effect on the contents of the bowel, emulsifying the stool and making it more slippery, thereby decreasing the resistance to its passage. Or at least, this is the theory. The bowel produces enough mucus, and it would be surprising to consider that it might need some kind of help.
Apart from being insidiously carcinogenic, hydrocarbon-based lubricant laxatives have all kinds of other side effects:
Like the osmotic and bulk-forming laxatives, these drugs aim to increase the water content of stool; but they achieve this without as much interference with the total bowel water per se. Instead, they increase the access of the existing water to the stool, separating its particles and decreasing its viscosity by their surfactant effects.
This drug is relatively safe, but still has some adverse effects:
Bowel stimulants could equally be rebranded as "bowel irritants", "colon botherers" or "intestinal agitators". There are several chemical families, which occasionally include surfactants like docusate, perhaps because it is felt to have some sort of stimulant role.
These drugs act by a variety of mechanisms, which are not very well described in the literature. The best you tend to get is a paragraph or two, alluding to effects without describing their mechanism. For example, Godding (1988) mentions that polyphenolic drugs (eg. bisacodyl) act by increasing the permeability of the gut mucosa, by inhibiting enterocyte Na+/K+ ATPase, and by increasing gut motility. Senna on the other hand induces the net secretion of fluid into the colon. How does it do that? Hands are waved in the direction of prostaglandins and serotonin. We can console ourselves with the thought that something like this could never possibly become the topic of an exam question.
Adverse effects are somewhat better documented:
These are relatively novel drugs which increase the secretion of water into the gut lumen, mainly by targeting chloride-mediated water uptake.
Though one might expect some metabolic alkalosis to develop as the result of all this chloride loss, in actual fact these drugs are generally well tolerated, presumably because one would be able to titrate the dose (profuse chloride-wasting watery diarrhoea would not be the desired endpoint).
This mechanism underlying the prokinetic effects of this group are well described in Gwynne & Bornstein (2019). In short, serotonin is an important signalling molecule in the gut, and in fact about 90% of the serotonin in the body is synthesised by mucosal enterochromaffin cells. Its main role appears to be as a neurotransmitter for myenteric neurons, and it is therefore involved in mediating the process of peristalsis, including the migratory motor complex and the myenteric reflex. Thus, to activate 5-HT4 receptors means to stimulate peristalsis. Several agents are available to achieve this:
There are many relative substances, such as mosapride and velusetrag, which do not have any hideous adverse effects, and which are in routine use around the world. It would be unfair to associate these newer safer drugs with the memorable adverse effects of the older drugs, which are:
It is not the intention of this short section to cover the pharmacology of macrolides, as most of them are usually used as antibiotics. Thankfully, there is some literature (eg. Peeters, 1993) that focuses specifically on their prokinetic properties.
The mechanism of prokinetic action of macrolides is related to their ability to act as motilin receptor agonists. Motilin is a peptide hormone which acts at multiple levels of the gut, from the antrum down (the only region which does not seem to respond is the ileum, which does not express motilin receptors). Activiating motilin receptors stimulates contraction by activation of smooth muscle L-type calcium channels, which manifests as increased antral activity, increased gastric emptying, and more high-amplitude propulsive contractions (Phase III of the migratory motor complex). If that sounds attractive, and one begins to wonder whether we really need to rely on the side-effects of antibiotics for these effects, one would be pleased to learn that there are motilin receptor agonists with no antibiotic activity, such as camincinal and mitemcinal (Sanger et al, 2012), some of which might eventually reach the market.
Macrolides are an old antibiotic class, and are not without their side-effects.
Acetylcholine is a major neurotransmitter for the intrinsic nervous system of the gut, and so it theoretically it would make some sense that we should look at using it as an instrument to reawaken colonic inertia. Practically, in the ICU, this use remains mainly in the realm of avoiding and preventing anticholinergic effects, rather than therapeutically using pro-cholinergic medications. The reason for this is that cholinergic prokinetics are too effective. For most intensivists, they represent the nuclear option.
Acetylcholinesterase inhibitors increase the availability of synaptic acetylcholine, whereas the direct agonists just bind straight to the muscarinic receptors, but the mechanism of effect beyond this is basically the same. To reduce the articles by Sanders et al (2016) and Eglen (2001) into some easily remember points:
Side effects? All of the effects are side effects. A reasonable person, reviewing the list of physiological reactions from the administration of these substances, would be forced to conclude that, whenever they are used for a specific indication, so many things inadvertently happen that the vast majority of the resulting outcomes are undesirable. The parasympathetic nervous system is vast and all-knowing, and to make it angry with a potent stimulant would obviously result in a million different effects. To name just a few, moving in the direction from head to toe,
It would be amiss to leave these drugs out of the discussion, as they do often come in handy even though their mechanism of action is not "prokinetic" per se. They do increase motility, but only by restoring it to some normal level in scenarios where the motility was impaired by opioids. Townsend et al (2004) describes the mechanisms of this impairment in some detail. In summary, δ- and κ-opioid receptors seem to be expressed in the nerves of the myenteric plexus of the small and large intestine, and their activation produces a direct activation of smooth muscle cells, leading to a constant tonic contraction of smooth muscle, and this sustained contraction inhibits normal peristaltic activity. There does not appear to be any tachyphylaxis or tolerance for this effect, which means that even veteran opium fiends develop constipation.
To defeat this, two main agents are available:
The side effects of these drugs are basically extensions of their desired effect: