This articles looks at the pharmacology of antidiarrhoeal drugs; exploring the classes of drugs used in the management of this common condition.

The ubiquity of diarrhoea among the populace, for lifestyle as well as pathological reasons, makes it a highly pertinent area of study. We’re going to take a look at this pertinence, by first understanding diarrhoea itself, including its causative and prevention factors, and later going on to look at the pharmacology of antidiarrheal drugs. Toward the latter part of this section, we’ll look at typical management strategies of diarrhoea before concluding with assessment questions on this entire piece. This section aims to inform your understanding of this condition given its prevalence in communities at home and abroad.

Understanding Diarrhoea

Deriving from the Ancient Greek, dia “through” and rheo “flow”, diarrhoea is a condition defined as having at least three bowel movements per day in some form. As such, the long-term consequences of this condition results in marked dehydration, which can further degenerate into symptoms of tachycardia, loss of consciousness, and alterations in one’s personality. The prevalence of diarrhoea in the developing world results in the deaths of millions of people on an annual basis. Closer to home, this condition remains more of a domestic lifestyle nuisance, but still needs to be treated with the same level of importance.

Causes of Diarrhoea

The most common cause of diarrhoea is gastroenteritis, a condition whereby the intestines become contaminated by an infection; bacterial, viral or parasitic. Viral gastroenteritis is much more common among children than bacterial causes. Campylobacter jejuni is the commonest cause of bacterial gastroenteritis in developed countries.

The cause of gastroenteritis itself usually comes water or food hitherto contaminated by the infected stool or, alternatively, directly from another individual. The severity of the diarrhoea is often indicative of its cause. Cholera, for example, usually results in watery stools of short duration. Dysentery is the name applied to diarrhoea accompanied by blood.

However, there are also non-infectious causes of diarrhoea, such as those derived from inflammatory bowel disease, irritable bowel syndrome, and hyperthyroidism, among others. Certain drugs, for example, such as magnesium salts, cytotoxic agents, α and β blockers, and broad-spectrum antibacterial drugs, have the potential to cause diarrhoea. Antibacterial treatment is, though, associated with Clostridium difficile colitis.

Prevention of Diarrhoea

The standard methods used involve enhancing the quality of water, sanitation technique, and, of course, hand washing. In addition, breastfeeding mothers are recommended to avail of the Rotavirus vaccination, offered in formulations such as Rotarix and RotaTeq. The importance of this vaccination for children reflects the highly contagious nature of this virus, as it remains just as contagious regardless of sanitation and water quality of a particular country. A new vaccination developed in India, Rotavac, has proven to harbour an excellent safety and efficacy profile – find out more about this latest development here.

Drugs Used in Treatment of Diarrhoea

We’re going to look at two main classes of drugs used in the treatment of diarrhoea. Understanding the pharmacology of antidiarrheal drugs informs your knowledge about the overall management of this condition. The two classes we’ll look at include:

ü Opioids
ü Adsorbent & Bulking Agents
 

Opioids

Examples: Loperamide, Diphenoxylate, Codeine Phosphate

Opioids have become a mainstay in the treatment of diarrhoea, acting through binding to u receptors on neurons in the submucosal neural plexus of the intestinal wall. This anti-motility action enhances segmental contraction of the colon, thereby inhibiting propulsive small intestine and colonic action. In other words, action on μ receptors prolongs the transit time for faeces in the intestines. This difference in transit time is crucial to provide patients the opportunity to replace fluids otherwise lost during their diarrhoeal phases as well as providing the time to consolidate intestinal contents. By drawing fluid out of the stool, you stop the formation of loose or liquid stools.

Let’s take a look at some of the main points you need to know:

  • Loperamide (Imodium), a piperadine derivative, along with codeine and diphenoxylate, remain the main antidiarrheal drugs.
  • Diphenoxylate is used in combination with atropine as co-phenotrope.
  • Most of these drugs have short half-lives (approx. 5 hours) though Loperamide has a more rapid onset of action and a longer half-life of 11 hours, giving it a longer duration of action.
  • Loperamide is more selective for the gut as it has a high first-pass metabolism that limits systemic absorption. This also makes dependence less of a problem.
  • Loperamide also has considerable anti-muscarinic activity which has the effect of inhibiting peristaltic contractions. This same effect is achieved by atropine in co-phenotrope.
  • Loperamide is a substrate of P-glycoprotein so the concentration of Loperamide will increase if given with a P-glycoprotein inhibitor such as Quinidine, Ritonavir, Omeprazole and Ketoconazole. Despite misconceptions, Loperamide will cross the blood-brain barrier if taken with one of these P-glycoprotein inhibitors, as the latter acts to pump Loperamide back out of the brain as it attempts to enter.
  • Diphenoxylate is metabolised in the body to yield the active ingredient Difenoxin.

Unwanted effects of opioid drugs include constipation, abdominal pain, nausea, dizziness, and a mild risk of dependence.

Adsorbent & Bulking Agents

Examples: Kaolin, Ispaghula, Methylcellulose

Though rare, Morphine has sometimes been employed in the treatment of diarrhoea in combination with Kaolin. Kaolin (Hydrated Aluminium Silicate) is an adsorbent that is relatively ineffective and not recommended in the treatment of acute diarrhoea.

Ispaghula and Methylcellulose are bulking agents that augment faecal consistency in diarrhoea-dominant irritable bowel syndrome patients (IBS-D). In addition, these bulking agents have also been used in patients with an ileostomy or colostomy. These antidiarrheal medications are, however, not recommended in the treatment of acute diarrhoea.
 

Management of Diarrhoea

Now that we have covered the pharmacology of antidiarrheal drugs, we can now take a look at how diarrhoea is actually managed.

  • In developed countries, the vast majority of people with infective diarrhoea, who are otherwise fit and healthy individuals, simply only require high oral fluid intake. Fluid and electrolyte balance remain particularly important for both children and the elderly, who are more likely to dehydrate at a significantly quicker rate.
  • Oral rehydration solutions, in combination with zinc tablets, have been responsible for saving 50 million children in the last 25 years alone. Replacement of electrolytes, therefore, is just as important as fluid replacement. In severe dehydration, intravenous fluids may be required.
  • Should an antidiarrheal medication be required; an opioid is sufficient for mild to moderate diarrhoea. However, these drugs should be avoided in patients with dysentery because prolonging contact of the contaminant with the intestinal mucosa can be damaging. Opioids are also not recommended in young children as they are known to cause ileus with severe abdominal distention.
  • Antibacterial prophylaxis can be used to avert Traveller’s Diarrhoea in prospective travellers visiting high-risk destinations. Co-trimoxazole (Trimethoprim/Sulfamethoxazole) or Ciprofloxacin are most often recommended depending on the location the individual is travelling to. In addition, the antibacterial can be administered at the first sign of illness and it will reduce the duration of the diarrhoea.
  • Diarrhoea may also be caused by antibacterials. Such antibacterial-induced diarrhoea usually resolves upon cessation of the provoking drug. In severe cases, or when Clostridium difficile colitis is suspected or Clostridium difficile has been detected in faeces, treatment can commence with oral Metronidazole or Vancomycin.
  • In patients suffering from inflammatory bowel disease, the diarrhoea in question needs to be managed by treating the underlying condition. Antidiarrheals, therefore, should not be used in active inflammatory bowel disease, due to the risk of precipitating toxic megacolon.

This completes our brief overview of the management of diarrhoea. As you can see, treatment invariably depends on the cause of the diarrhoea itself, and these individual causes are widespread. Remaining familiar with these differences is key to your success at understanding which antidiarrheal drug is required.

Assessment Questions

This section reviews both the pharmacology of antidiarrheal drugs as well as the management of diarrhoea itself. There are, as usual, fifteen questions, each of which requires either a True or False answer. You can find the answers located below.

  1. Infectious diarrhoea is chiefly caused by bacteria in children (<2 years).
  2. Use of broad-spectrum antibacterial drugs may result in pseudomembranous colitis.
  3. Antidiarrhoeal drugs may increase the residence of entero-invasive bacteria in the gut.
  4. Oral rehydration powders must be reconstituted with water to give a hypertonic solution.
  5. Co-trimoxazole is recommended for the treatment of Traveller’s Diarrhoea.
  6. Loperamide has a longer half-life and longer duration of action compared to other opioid antidiarrhoeal medications.
  7. Antidiarrhoeal drugs, particularly Loperamide, are recommended in patients with Crohn’s disease.
  8. Diphenoxylate should be avoided in patients with dysentery.
  9. Methylcellulose is a bulking agent used in the treatment of acute diarrhoea.
  10. Loperamide has considerable muscarinic activity.
  11. Metronidazole is recommended in the treatment of Clostridium difficile colitis.
  12. Cholera results in loose watery stools of short duration.
  13. Kaolin is an adsorbent that is moderately effective in the treatment of acute diarrhoea.
  14. Loperamide is less selective for the gut due to high first-pass metabolism.
  15. In developed countries, Campylobacter jejuni is the commonest cause of bacterial gastroenteritis.

Answers:
1. False 2. True 3. True 4. False 5. True 6. True 7. False 8. True 9. False 10. False 11. True 12. True 13. False 14. False 15. True

Conclusion

This pharmacology of antidiarrheal drugs is invariably interconnected with the cause of the diarrhoea itself. We began this section by looking at these causes, as well as the prevention and prevalence of this condition, before moving on to the two major classes of drugs used in its treatment: opioids and bulking agents. Treatment overwhelmingly reflects the former class, with opioids informing much of what you’ll learn in the overall management of diarrhoea.

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