Stomach and Gut Medicines

TL;DR. Proton pump inhibitors are among the most prescribed drugs in the world and among the most over-prescribed: they are excellent for the conditions they are for and are routinely continued for years without review. They cause rebound acid hypersecretion on stopping, which makes people think they still need them, so they need tapering rather than stopping. Peptic ulcers are mostly caused by Helicobacter pylori and NSAIDs, not by stress or spicy food, a discovery its author demonstrated by drinking a culture of the bacterium. And loperamide, an ordinary anti-diarrhoeal, is an opioid that has killed people who took it at very high doses.

1. The acid problem

Your stomach makes hydrochloric acid at pH 1.5 to 3.5, from parietal cells using an enzyme called the hydrogen-potassium ATPase, or proton pump (Chapter 10). Three signals drive it: gastrin (from food), histamine (via H2 receptors), and acetylcholine (vagal). The proton pump is the final common step, which is why blocking it is more effective than blocking any single signal.

Acid causes trouble when it goes where it should not (reflux) or when the stomach's own defences fail (ulcers).

2. The acid-suppressing drugs

Alginates deserve a mention because they work by an unusual mechanism: on contact with stomach acid, alginate forms a gel raft that floats on the stomach contents and physically blocks reflux. This makes them useful for reflux specifically, and they work well after meals and at bedtime.

Ranitidine was withdrawn worldwide in 2019 to 2020 after NDMA, a probable human carcinogen, was found in products, apparently from degradation of the molecule itself over time and at temperature (Chapter 63). Famotidine replaced it.

How to take a PPI properly

This is one of the most commonly got-wrong instructions in medicine.

PPIs only inhibit pumps that are actively working. Pumps are activated by food. So:

Take a PPI 30 to 60 minutes BEFORE a meal, usually breakfast. Taking it at bedtime on an empty stomach, or with the meal, substantially reduces its effect. Studies find a large proportion of patients take PPIs incorrectly, and it is a common reason for apparent treatment failure.

They also take 3 to 5 days to reach full effect, because they only disable the pumps currently active, and new pumps are being made continuously. A PPI is not a rescue medicine; antacids and alginates are.

3. Reflux and heartburn

Gastro-oesophageal reflux disease (GORD/GERD) is acid entering the oesophagus, which has no protection against it. Symptoms: burning behind the breastbone, acid taste, worse lying down or bending, sometimes cough, hoarseness, or a sensation of a lump.

Non-drug measures, ranked by evidence:

1. Weight loss if overweight. The best-evidenced intervention by some distance.
2. Raise the head of the bed by 15 to 20 cm using blocks under the legs. Extra pillows do not work, because they bend you at the waist.
3. Do not eat within 3 hours of lying down.
4. Stop smoking, which weakens the lower oesophageal sphincter.
5. Identify personal triggers. Common ones are alcohol, caffeine, chocolate, fatty and fried food, spicy food, citrus, tomato, and mint. Blanket avoidance of all of them is not supported; individual triggers vary and unnecessary restriction is common.
6. Smaller meals, and avoid tight clothing.

Red flags requiring investigation rather than self-treatment: difficulty or pain swallowing, unintentional weight loss, vomiting blood or coffee-ground material, black tarry stools, anaemia, persistent vomiting, a new onset over the age of 55, or symptoms not responding to treatment.

4. Peptic ulcers, and one of medicine's best stories

Until the 1980s, ulcers were attributed to stress and diet, and treated with acid suppression, bland diets, and sometimes surgery.

Barry Marshall and Robin Warren in Perth proposed that a spiral bacterium, later named Helicobacter pylori, caused most peptic ulcers. The idea was widely rejected: the stomach was believed too acidic for bacteria.

In 1984, unable to produce an animal model and unable to get ethical approval, Marshall drank a culture of H. pylori. He developed gastritis within days, demonstrated the bacterium in his own biopsies, and cured himself with antibiotics. They received the Nobel Prize in 2005.

The result: peptic ulcer disease went from a chronic relapsing condition managed for life to a curable infection. Elective ulcer surgery has essentially disappeared.

Causes of peptic ulcer, in order:

1. H. pylori infection (roughly 70 to 90 percent of duodenal ulcers, though falling in wealthy countries as infection rates decline)
2. NSAIDs and aspirin (Chapter 66)
3. Rarer: Zollinger-Ellison syndrome, severe physiological stress in critical illness

Not causes: ordinary psychological stress, spicy food, and acidic food, though all can worsen symptoms of an existing ulcer.

H. pylori eradication uses a PPI plus two antibiotics for 7 to 14 days (commonly amoxicillin plus clarithromycin or metronidazole), with quadruple regimens where resistance is high. Clarithromycin resistance is rising and is changing first-line choices in many countries.

5. PPIs: the over-prescription problem

PPIs are genuinely excellent drugs. They are also continued far beyond their indication in a very large proportion of users, with estimates that 25 to 70 percent of prescriptions lack a clear ongoing indication.

Legitimate long-term use: Barrett's oesophagus, severe erosive oesophagitis, Zollinger-Ellison syndrome, and gastroprotection for people at high GI risk who must continue NSAIDs, aspirin, or anticoagulants.

Associations with long-term use, and this list needs careful reading:

The honest summary: PPIs are safe and effective for their indications, the long-term associations are mostly modest and observational, and the sensible response is periodic review of whether the drug is still needed rather than alarm.

Rebound acid hypersecretion is the practical problem in stopping. Suppressing acid raises gastrin, which increases the number of parietal cells. Stop the PPI and those cells produce more acid than before, for weeks. A famous trial demonstrated this in healthy volunteers who had never had reflux: after eight weeks of PPI, a substantial proportion developed heartburn on stopping.

So people conclude they still need the drug when they are actually experiencing withdrawal.

How to stop: step down rather than stop, halve the dose for two to four weeks, then alternate days, then switch to an H2 blocker or on-demand antacids, and expect a few weeks of worse symptoms. Do this with your prescriber.

6. Constipation

Covered nutritionally in Chapter 25 and Chapter 28; the drugs:

Practical points:

• Food and fluid first: fibre to around 30 g gradually, adequate fluid, and physical activity.
• Bulk-forming laxatives without enough fluid make constipation worse, which is the commonest way fibre advice backfires.
• Macrogol (PEG) is first-line in most guidelines and has the best evidence, including in children.
• Stimulant laxatives are not habit-forming in the way folklore suggests. The old belief that senna damages the bowel or creates dependence is not supported for normal use, though chronic high-dose use is best avoided.
• Opioid-induced constipation needs a stimulant from day one, not a bulking agent (Chapter 68).
• In pregnancy: bulk-forming first, then lactulose or macrogol; senna is used in late pregnancy where needed.
• Red flags: new constipation over 50, blood, weight loss, or a change in bowel habit lasting more than three weeks needs investigation.

7. Diarrhoea

The priority is fluid, not stopping the diarrhoea. Oral rehydration solution is the treatment that saves lives, exploiting glucose-coupled sodium absorption (Chapter 10).

Loperamide (Imodium) slows gut motility by acting on opioid receptors in the gut wall. At normal doses it does not cross the blood-brain barrier meaningfully and has no central effects.

The serious caveat: at very high doses, loperamide does reach the brain and heart, and it has been misused as an opioid substitute. High doses cause dangerous cardiac arrhythmias (QT prolongation, torsades de pointes) and deaths are documented. The FDA issued warnings and imposed packaging limits in 2017 to 2019. At the doses on the packet it is safe; the abuse pattern involves dozens of times the recommended dose.

When NOT to use loperamide:

• Bloody diarrhoea or high fever, which suggests invasive bacterial infection. Slowing transit can prolong the illness and, in E. coli O157, increase the risk of haemolytic uraemic syndrome.
• Suspected C. difficile.
• Children under 12, where it is not recommended.
• Inflammatory bowel disease flares, where it can precipitate toxic megacolon.

When it is reasonable: short-term symptom control in uncomplicated travellers' diarrhoea and in functional bowel disorders, alongside rehydration.

Bismuth subsalicylate (Pepto-Bismol) has antisecretory and antimicrobial effects, is useful for travellers' diarrhoea, and turns the tongue and stools black, which is harmless and alarming. It contains salicylate, so avoid in children and in aspirin allergy.

8. Nausea and vomiting

Different causes respond to different drugs, which is why one anti-emetic does not fit all:

Metoclopramide and prochlorperazine can cause extrapyramidal reactions: acute dystonia with muscle spasm of the neck, jaw, or eyes, most commonly in young people and often mistaken for a seizure or a psychiatric event. It is frightening, reversible with an anticholinergic (procyclidine), and the reason metoclopramide is limited to five days' use in the EU.

Ondansetron causes constipation and can prolong the QT interval.

9. Practical guidance

• Take a PPI 30 to 60 minutes before breakfast, and expect a few days for full effect.
• Use antacids or alginates for immediate relief; they are what PPIs are not.
• Review long-term acid suppression annually. Ask whether it is still needed.
• Taper rather than stop, and expect rebound.
• Do not treat persistent reflux for months without assessment, particularly over 55 or with any red flag.
• Macrogol for constipation, with enough fluid.
• Rehydration first for diarrhoea; loperamide only when there is no fever or blood.
• Do not exceed the loperamide packet dose. It is an opioid, and at high doses it is a cardiac poison.

10. The bottom line

• Antacids and alginates work in minutes; PPIs take days and are far more powerful. Different jobs.
• PPIs must be taken 30 to 60 minutes before food to work properly, and a large proportion of people take them wrongly.
• Peptic ulcers are caused by H. pylori and NSAIDs, not stress or spice, and eradication cures them. Barry Marshall proved it by drinking the bacterium.
• Long-term PPI use is common, often unnecessary, and associated with modest risks. Review it, and taper rather than stop, because rebound acid production makes stopping feel like relapse.
• Fibre and fluid before laxatives; macrogol first-line; stimulants for opioid constipation from day one.
• Loperamide is an opioid. Safe at packet doses, cardiotoxic and occasionally fatal at the doses used in misuse, and inappropriate for bloody or feverish diarrhoea.

Sources and notes

Doses, cautions, and interactions follow the British National Formulary and the electronic Medicines Compendium; US figures follow FDA labelling. Gastric acid physiology and the proton pump follow standard gastroenterology texts. PPI timing before meals follows Katz, Gerson, and Vela's ACG guideline and pharmacokinetic studies showing reduced efficacy with incorrect timing. Ranitidine NDMA withdrawal follows EMA and FDA recall documentation from 2019. H. pylori discovery follows Marshall and Warren's 1984 Lancet paper and Marshall's self-experimentation, recognised by the 2005 Nobel Prize; eradication regimens follow Maastricht VI and ACG guidance. PPI long-term association reviews follow Freedberg, Kim, and Yang's AGA best practice advice, which concluded most associations are weak and confounded. Rebound acid hypersecretion follows Reimer et al., Gastroenterology, 2009, in healthy volunteers. Laxative evidence follows NICE guidance and Cochrane reviews, with macrogol first-line. The absence of senna-induced bowel damage at normal use follows Wald's reviews. Loperamide cardiac toxicity at high doses and the FDA packaging restrictions of 2017 to 2019 follow FDA safety communications and case series. Oral rehydration solution follows WHO formulation guidance. Metoclopramide extrapyramidal reactions and the EU five-day restriction follow the 2013 EMA review.

Open questions. How much of the long-term PPI risk literature reflects the drug rather than the reasons people take it is unresolved, and the honest answer is that most associations are modest and confounded.

👉 Next: antibiotics.