Antidiarrhoeals

Causative factors

Clostridium difficile (C.difficile)

C.difficile infection occurs when normal gut microbiota are suppressed, allowing levels of toxin producing strains of C. difficile to increase. The toxin damages the lining of the colon and causes diarrhoea. 

There is a higher risk of C.difficile infection after prolonged antibiotic usage (especially broad spectrum antibiotics) and/or hospital admissions. Antibiotics such as vancomycin (PO) and fidaxomicin (PO) are commonly used to treat C.difficile.

• Vancomycin is a tricyclic glycopeptide antibiotic that inhibits the synthesis of the cell wall in sensitive bacteria. When vancomycin is taken orally, it is not absorbed into the systemic circulation and acts locally on the intestinal mucosa.
• Fidaxomicin is a narrow spectrum antimicrobial drug with bactericidal activity against c.difficile and inhibits RNA synthesis by bacterial RNA polymerase. Fidaxomicin is also poorly absorbed from the GI tract so is only indicated in c.difficile infections where it acts locally on the gut mucosa.

Proton pump inhibitors or H2 receptor antagonists should be stopped unless there is a clear indication, as both drug classes suppress gastric acid secretion and may contribute to growth of the c.difficile strain.

Medication

Newly initiated medications should be considered as potential causes for new diarrhoea.

Treatment Options

Oral Rehydration Therapy

Oral rehydration therapy involves use of a combination of electrolytes that stimulate water and electrolyte absorption from the GI tract, therefore preventing or reversing dehydration in diarrhoea. A commonly seen example is Dioralyte sachets which contain sodium, potassium and glucose. 

The mechanism of action of Dioralyte is described as follows: 

Sodium and glucose are actively transported via the sodium-glucose transporter pump into the enterocytes. 

Sodium is then extruded into the intercellular spaces and the resulting osmotic gradient causes water and electrolytes to be reabsorbed from the gut and into the circulation.

Oral rehydration therapy contains sodium and should therefore be used with caution in patients on a low-sodium diet. Furthermore, Dioralyte contains potassium, so it should be used cautiously in patients at risk of hyperkalaemia. Alternative oral rehydration therapies that do not contain potassium—such as St Mark’s Solution—are available.

In high stoma output and/or short bowel syndrome, Dioralyte is often used at double the concentration (i.e. 1 sachet in 100ml of water rather than 1 sachet in 200ml of water) to increase absorption of water and electrolytes across the gut lumen and reduce the stoma output, this is off label use. 

Created in BioRender. Boucher, M. (2025) https://BioRender.com/om4zdiu

Fig 1: Mechanism of action of oral rehydration solutions

Antimotility Therapy

The mainstay of antimotility therapy includes loperamide and codeine. Loperamide is preferred over codeine for the treatment of diarrhoea due to the risk of drug dependence and withdrawal effects if therapy is stopped, alongside risk of respiratory depression and death in overdose.

Loperamide

Loperamide is a synthetic opioid which inhibits gut motility by binding to opiate receptors in the gut wall. Loperamide does not cross the blood brain barrier therefore does not elicit the analgesic effect seen with opiates. 

Cautions for use of loperamide include:

• Loperamide should be avoided in suspected inflammatory diarrhoea, confirmed bacterial enterocolitis caused by invasive organisms and in pseudomembranous colitis associated with the use of broad- spectrum antibiotics. 
• In overdose or in high doses of >16mg/day (common when used for high output stoma) ECG monitoring is advisable. Cardiac events including QT interval, QRS complex prolongation and torsades de pointes have been reported in overdose.

Codeine

Codeine can also be used to treat diarrhoea and high output stoma. Codeine crosses the blood brain barrier therefore acts at central and peripheral μ-opioid receptors, meaning it does ilicit an analgesic effect and can cause dependence. Codeine is metabolised in the liver to form morphine via enzyme CYP2D6 as shown in figure 1 below.

There is a risk that ultrarapid metabolizers of codeine will have more rapid and complete metabolism of codeine to morphine leading to increased risk of overdose. Codeine is contraindicated in breastfeeding mothers due to the risk of ultrarapid metabolizers producing breast milk with higher levels of morphine

Created in BioRender. Boucher, M. (2025) https://BioRender.com/2b9t0th

Fig 2: Mechanism of action of anti-motility agents

References

1. BNF online Diarrhoea (Acute) available from Diarrhoea (acute) | Treatment summaries | BNF | NICE accessed 13/8/24
2.  SPC Loperamide Last updated on emc: 04 Aug 2023. Available from https://www.medicines.org.uk/emc/product/10420/smpc accessed 15/8/24
3. SPC Dioralyte blackcurrant sachets. Last updated on emc: 18 Jan 2024. Available from: Dioralyte Blackcurrant Sachets (GSL) – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk). Accessed 15/8/24.
4. SPC Codeine Phosphate 30mg Tablets – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) accessed 1/9/24
5. Clostridium difficile infection: How to deal with the problem. DoH. Dec 2008. Available from: Clostridium_difficile_infection_how_to_deal_with_the_problem.pdf (publishing.service.gov.uk)
6. BNF Gastro-intestinal system infections, antibacterial therapy. Available from: Gastro-intestinal system infections, antibacterial therapy | Treatment summaries | BNF | NICE accessed 14/8/24
7. Spc Vancomycin 125 mg hard capsules – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) accessed 1/9/24
8. SPC Fidaxomicin 200mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) accessed 1/9/24