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PH6.3 | PH6.3 | Diarrhoea Pharmacotherapy — SDL Guide — SDL Guide (Part 2)

ORS and Zinc — Cornerstone of Diarrhoea Management

Oral rehydration therapy is one of the greatest public health achievements of the 20th century. Before ORS was developed in the 1960s–1970s, cholera carried a case fatality rate of 50–70%; with correctly administered ORS, this fell to below 1%. The pharmacological principle underlying ORS — exploiting the sodium-glucose cotransporter that remains functional even when secretory toxins are maximally activating chloride channels — is a textbook example of using fundamental physiology to overcome a pathophysiological process. Understanding this mechanism explains why ORS must contain glucose (plain water does not work for the same reason), why the glucose:sodium ratio in the formula is not arbitrary, and why reducing the osmolarity of the WHO formula from 311 to 245 mOsm/L in 2002 reduced stool output and vomiting without causing hyponatraemia.

Oral rehydration therapy is one of the greatest public health achievements of the 20th century. Before ORS was developed in the 1960s–1970s, cholera carried a case fatality rate of 50–70%; with correctly administered ORS, this fell below 1%. The pharmacological principle underlying ORS — exploiting the sodium-glucose cotransporter that remains functional even when secretory toxins are maximally activating chloride channels — is a textbook example of using physiology to overcome pathology.

The WHO low-osmolarity ORS formula (2002, current standard):
- Glucose: 75 mmol/L
- Sodium: 75 mmol/L
- Chloride: 65 mmol/L
- Potassium: 20 mmol/L
- Citrate (bicarbonate equivalent for acidosis): 10 mmol/L
- Total osmolarity: 245 mOsm/L (reduced from the original 311 mOsm/L formula — the lower osmolarity reduces stool output and vomiting without increasing hyponatraemia risk)

Mechanism: When glucose and Na⁺ are presented together at the apical membrane of the enterocyte, the SGLT1 (sodium-glucose linked transporter 1) co-transports them at a ratio of 2 Na⁺: 1 glucose electrogenic transport. This Na⁺ entry drives the basolateral Na⁺/K⁺-ATPase to pump Na⁺ out of the cell, creating an electrochemical gradient that pulls Cl⁻ and water from the lumen into the epithelial cell, and then into the bloodstream. Crucially, SGLT1 activity is independent of cAMP and cGMP — so even when cholera toxin has permanently activated adenylate cyclase and Gs protein to maximally secrete Cl⁻, the glucose-driven absorption pathway remains intact. This is why ORS works in cholera and why glucose must be present in the formula (water alone, without glucose, does not drive sufficient Na⁺ absorption).

Zinc supplementation (for children under 5 years): WHO/UNICEF recommends zinc 20 mg/day orally for 10–14 days alongside ORS for children with acute diarrhoea. Zinc:
- Reduces stool output and episode duration by approximately 25%.
- Reduces the risk of subsequent diarrhoeal episodes for 2–3 months (restores intestinal mucosal immunity and zinc-dependent metalloenzymes).
- Is particularly important in zinc-deficient populations (most Indian children in diarrhoea-endemic regions).

Home-made ORS (UNICEF formula): 1 litre of clean water + 6 level teaspoons of sugar + half a teaspoon of salt — a practical emergency formula when packets are unavailable. Not ideal (lacks K⁺ and citrate) but life-saving in resource-limited settings.

Anti-Motility Agents — Loperamide and Diphenoxylate

Anti-motility agents reduce diarrhoea by slowing intestinal peristalsis and increasing anal sphincter tone, thereby reducing stool frequency and volume loss. They are highly effective in the appropriate context — notably non-invasive watery diarrhoea and travellers' diarrhoea in adults — but they represent one of the most dangerous prescribing errors when given for invasive diarrhoea, where reducing gut motility traps invasive organisms in the colon and converts a self-limiting dysentery into a life-threatening complication.

Loperamide is the preferred anti-motility agent. It is a synthetic peripheral mu-opioid receptor agonist that acts on mu-opioid receptors in the myenteric plexus of the enteric nervous system: (a) it reduces longitudinal and circular smooth muscle activity, slowing peristalsis; (b) it increases internal anal sphincter tone, reducing faecal urgency; and (c) it reduces intestinal secretion (via mu-opioid receptors on intestinal epithelial cells, reducing cAMP-driven secretion). At therapeutic doses, loperamide is highly lipophilic but is a substrate of P-glycoprotein at the blood-brain barrier, which actively effluxes it from the CNS — so it produces no central opioid effects (no analgesia, sedation, euphoria, or addiction risk) in adults with an intact BBB. It does not require a schedule-H prescription for this reason.

Adverse effects: Constipation, abdominal distension, dry mouth (mild). Rare: toxic megacolon (if given in invasive diarrhoea). Overdose can cause CNS toxicity (naloxone-reversible) — especially relevant in young children whose BBB is less mature.

Absolute contraindications:
- Invasive/bloody/dysenteric diarrhoea with fever: trapping Shigella, Salmonella, Campylobacter, EIEC, or E. coli O157:H7 in the colon prolongs infection, promotes bacteraemia, and causes toxic megacolon or haemolytic uraemic syndrome.
- Children under 2 years: immature BBB → central opioid toxicity risk.
- WHO does not recommend loperamide in children under 5 with acute diarrhoea (racecadotril is the preferred alternative in paediatric secretory diarrhoea).

Diphenoxylate + atropine (Lomotil): Diphenoxylate is an opioid agonist with partial CNS access (more lipophilic than loperamide, partially penetrates BBB). Atropine is added in subtherapeutic quantities to make the combination unpleasant to abuse in large doses (anticholinergic dysphoria + dry mouth if misused). It is a schedule H drug. Same contraindications as loperamide. Less preferred than loperamide due to CNS access.

Racecadotril (acetorphan): An enkephalinase inhibitor — it prevents the breakdown of endogenous enkephalins (endorphins) in the gut. Enkephalins, acting on mu and delta receptors on enterocytes, normally inhibit cAMP-driven Cl⁻ secretion. By blocking enkephalin degradation, racecadotril enhances this endogenous antisecretory effect without inhibiting motility. This distinction is clinically important for children: racecadotril reduces stool output without prolonging transit time, so even if there is a mild invasive component, it does not trap organisms in the colon the way loperamide does. Endorsed by the Indian Academy of Pediatrics and WHO as a useful adjunct to ORS in paediatric acute diarrhoea.

Antibiotic Therapy in Diarrhoeal Disease

Antibiotic therapy in diarrhoeal disease is indicated only for specific bacterial pathogens — it is not appropriate for viral diarrhoea (rotavirus, norovirus — no benefit, risk of microbiome disruption) or for most mild self-limiting diarrhoeas. The selection of antibiotic must be matched to the most probable pathogen based on clinical features, patient setting, epidemiology, and local resistance patterns. Empirical antibiotic use without this rational framework contributes directly to antibiotic resistance — already a major clinical problem in India where fluoroquinolone-resistant Shigella, Salmonella, and Campylobacter strains are increasingly prevalent. The key principle is specificity: not every diarrhoeal patient needs an antibiotic, and those who do need the right antibiotic for the right duration at the right dose.

Antibiotic therapy in diarrhoeal disease is indicated only for specific bacterial pathogens — it is not appropriate for viral diarrhoea (rotavirus, norovirus — no benefit, risk of microbiome disruption) or for most mild self-limiting diarrhoeas. The selection of antibiotic must be matched to the most probable pathogen based on clinical features, patient setting, epidemiology, and local resistance patterns. Empirical antibiotic use without this framework contributes to antibiotic resistance, which is already a major clinical problem in India with fluoroquinolone-resistant enteric pathogens.

Pathogen-matched antibiotic selection:

Condition/Pathogen	Antibiotic of choice	Alternative	Notes
Travellers' diarrhoea (non-bloody, non-febrile)	Ciprofloxacin 500 mg bd × 3 days	Azithromycin 1 g single dose	Rifaximin (non-absorbable) for non-invasive mild cases; fluoroquinolone resistance rising in South Asia
Shigella dysentery	Ciprofloxacin 500 mg bd × 5 days	Azithromycin 500 mg daily × 3 days	Ampicillin/cotrimoxazole resistance widespread; ceftriaxone for severe/systemic
Campylobacter enteritis	Azithromycin 500 mg daily × 3 days	Ciprofloxacin (high resistance in some regions)	High fluoroquinolone resistance in Campylobacter globally
Salmonella enterocolitis (non-typhoidal)	Usually self-limiting; antibiotics prolong carriage and not routinely given	Ciprofloxacin for high-risk (immunocompromised, sickle cell, prosthetic valves)	Do not give antibiotics to healthy adults with non-typhoidal Salmonella gastroenteritis
Giardia lamblia	Metronidazole 400 mg three times daily × 5 days	Tinidazole 2 g single dose	Nitazoxanide alternative
C. difficile — mild/moderate	Oral metronidazole 400–500 mg three times daily × 10 days	—	Stop the precipitating antibiotic; fidaxomicin for recurrence
C. difficile — severe (high WBC, rising Cr, severe colitis)	Oral vancomycin 125 mg four times daily × 10 days	Fidaxomicin	Metronidazole inferior to vancomycin in severe C. difficile
C. difficile — recurrent	Fidaxomicin 200 mg bd × 10 days	Faecal microbiota transplantation (FMT)	Bezlotoxumab (anti-toxin B antibody) for secondary prevention
Amoebiasis (E. histolytica)	Metronidazole 800 mg three times daily × 5–10 days	Tinidazole	Follow with luminal agent (diloxanide furoate) to eliminate cysts

Oral vancomycin in C. difficile: Oral vancomycin is NOT absorbed systemically (it has negligible oral bioavailability). Its antibacterial action is entirely within the colon — this is the only indication where a drug that is not absorbed systemically is prescribed orally to treat an infection.