Gastrointestinal drugs
Acid-Peptic, Antiemetic, Laxative, IBD and Motility Drugs: FCPS Part 1
PPIs, H2 blockers, antacids, Helicobacter eradication, antiemetics, laxatives, antidiarrhoeals and IBD drugs for FCPS Part 1, explained by mechanism. Covers PPI timing, cimetidine interactions, domperidone versus metoclopramide, loperamide, methylnaltrexone and sulfasalazine.
How the parietal cell makes acid
Histamine (H2, via cAMP), acetylcholine (M3) and gastrin (CCK2) all stimulate the parietal cell; the final common step is the H+/K+-ATPase (proton pump) in the secretory canaliculus. Blocking the pump therefore stops acid whatever the stimulus, which is why PPIs are the strongest acid suppressants.
Acid-suppressing and mucosal drugs
| Drug | Mechanism | Key points |
|---|---|---|
| PPIs (omeprazole, lansoprazole, pantoprazole, esomeprazole) | Prodrugs activated in the acid canaliculus; irreversibly bind active H+/K+-ATPase | Strongest; long-term hypomagnesaemia, hyponatraemia, B12 deficiency, fractures, *C. difficile*, pneumonia; omeprazole inhibits CYP2C19 (less clopidogrel activation) |
| H2 antagonists (famotidine, cimetidine) | Competitive H2 block | Weaker; good for nocturnal acid |
| Antacids | Neutralise acid | Aluminium hydroxide: constipation, delays gastric emptying, binds phosphate; magnesium: diarrhoea; chelate tetracyclines, quinolones, iron |
| Sucralfate | Polymerises in acid to coat the ulcer base | Constipation; binds other drugs |
| Misoprostol | PGE1 analogue: less acid, more mucus and bicarbonate | NSAID ulcer prevention; diarrhoea; abortifacient |
| Bismuth | Coats ulcer, kills *H. pylori* | Black tongue and black stools |
- PPI timing: PPIs bind only pumps that are actively secreting. Taken 30 minutes before breakfast, the drug peaks in blood just as the meal switches pumps on. Taken at bedtime on an empty stomach, few pumps are active and daytime acid is poorly controlled.
- Cimetidine inhibits hepatic CYP450 enzymes (and is anti-androgenic: gynaecomastia). A woman on warfarin who buys cimetidine sees her INR rise. Famotidine (and the former ranitidine) are more potent, do not inhibit CYP450 and are not anti-androgenic.
- Sucralfate with an H2 blocker or antacid: give 2 hours apart, because sucralfate needs acid to activate and also binds other drugs.
- Before caesarean section, an H2 blocker or PPI with sodium citrate raises gastric pH to reduce acid aspiration pneumonitis.
- Milk-alkali syndrome: heavy calcium carbonate antacid use with milk causes hypercalcaemia, metabolic alkalosis and AKI with suppressed PTH. Hypercalcaemia causes polyuria, volume loss raises bicarbonate reabsorption, and the alkalosis increases calcium reabsorption: a vicious cycle.
- Mifepristone (progesterone receptor antagonist) followed 24–48 hours later by misoprostol is used for medical termination of pregnancy and missed miscarriage. Misoprostol is contraindicated in a pregnancy that is to continue.
Helicobacter pylori and dyspepsia
- First-line eradication: PPI plus two antibiotics, usually amoxicillin with clarithromycin or metronidazole, for 7–14 days. Bismuth quadruple therapy (PPI, bismuth, tetracycline, metronidazole) for failure or penicillin allergy with resistance.
- Test of cure by urea breath test or stool antigen at least 4 weeks after antibiotics and 2 weeks off PPI (PPIs cause false negatives).
- Chronic *H. pylori* gastritis is the cause of gastric MALT lymphoma; eradication can make early lesions regress.
- Alarm features (age 55 or more with weight loss, dysphagia, iron deficiency, persistent vomiting, a mass) need urgent endoscopy, not empirical omeprazole, which can mask gastric cancer.
Exam trap Black stools during bismuth therapy are expected, but black stools with a falling haemoglobin are melaena until proved otherwise.
Antiemetics: match receptor to cause
| Drug | Receptor | Best for | Notes |
|---|---|---|---|
| Metoclopramide | D2 antagonist plus 5-HT4 agonist (prokinetic) | Gastric stasis, diabetic gastroparesis, migraine | Acute dystonia (young women); avoid in bowel obstruction and Parkinson disease; maximum 5 days |
| Domperidone | Peripheral D2 antagonist | Parkinson disease, gastroparesis | QT prolongation, galactorrhoea |
| Ondansetron | 5-HT3 antagonist (gut vagal afferents and CTZ) | Chemotherapy, post-operative | Constipation, headache, QT |
| Cyclizine, promethazine | H1 antagonist (antimuscarinic) | Motion sickness, vestibular, opioid nausea, bowel obstruction | Sedation |
| Hyoscine hydrobromide | Muscarinic antagonist | Motion sickness | Dry mouth |
| Prochlorperazine, haloperidol | D2 (CTZ) | Vertigo, metabolic or opioid nausea | EPS |
| Aprepitant | NK1 antagonist | Delayed chemotherapy vomiting | CYP3A4 interactions |
| Dexamethasone | Uncertain | Chemotherapy, raised ICP | |
| Erythromycin | Motilin agonist | Gastroparesis (prokinetic) | Tachyphylaxis |
- Domperidone barely crosses the blood–brain barrier, so it does not block striatal D2 receptors and causes few extrapyramidal effects. It still works on the chemoreceptor trigger zone, which lies in the area postrema outside the barrier. It is the antiemetic of choice in Parkinson disease, for example after cholecystectomy.
Laxatives
| Type | Examples | How they work |
|---|---|---|
| Bulk-forming | Ispaghula, bran | Retain water and increase stool mass; slow; can worsen opioid constipation |
| Osmotic | Macrogol (PEG), lactulose, magnesium salts | Non-absorbed solutes hold water in the colon by osmosis; lactulose also acidifies the colon, trapping ammonia as NH4+ (hepatic encephalopathy) |
| Stimulant | Senna, bisacodyl, sodium picosulfate | Stimulate myenteric plexus and secretion; for opioid constipation |
| Softeners | Docusate, arachis oil enema | Lower stool surface tension |
| Peripheral μ antagonists | Methylnaltrexone (SC), naloxegol | Block gut opioid receptors but do not enter the brain, so analgesia is preserved |
| Prokinetic and secretagogue | Prucalopride (5-HT4), linaclotide | Chronic constipation |
- Opioid constipation resistant to senna and macrogol in a patient whose pain must stay controlled: subcutaneous methylnaltrexone, after excluding obstruction.
Antidiarrhoeals
- Loperamide is a μ agonist that is pumped out of the brain by P-glycoprotein at the blood–brain barrier and is poorly absorbed, so it slows the gut without central effects at normal doses. Massive overdose causes arrhythmias. Avoid in bloody diarrhoea or infective colitis (toxic megacolon).
- Diphenoxylate with a sub-therapeutic dose of atropine: the atropine causes unpleasant anticholinergic effects at high doses, discouraging deliberate overdose. Dangerous in young children.
- Oral rehydration is the mainstay in children; bile acid sequestrants for bile acid diarrhoea.
Inflammatory bowel disease drugs
| Drug | Role | Adverse effects |
|---|---|---|
| 5-ASA (mesalazine; sulfasalazine = 5-ASA linked to sulfapyridine) | Ulcerative colitis induction and maintenance | Mesalazine: interstitial nephritis; sulfasalazine: oligospermia, rash, folate deficiency, agranulocytosis |
| Corticosteroids (prednisolone, IV hydrocortisone, budesonide) | Induction only | Steroid effects; budesonide has high first-pass metabolism |
| Thiopurines (azathioprine, mercaptopurine) | Steroid-sparing maintenance | Check TPMT first; myelosuppression, pancreatitis; allopurinol interaction |
| Methotrexate | Crohn maintenance | Marrow, liver |
| Anti-TNF (infliximab, adalimumab) | Severe or fistulating Crohn, UC rescue | TB reactivation |
| Vedolizumab, ustekinumab, JAK inhibitors | Gut-selective integrin, IL-12/23, JAK | Infection |
| Ciclosporin | Acute severe UC rescue | Nephrotoxicity, seizures |
- The sulfapyridine carrier causes sulfasalazine's sulphonamide-type effects, including reversible oligospermia. A man with infertility should switch to mesalazine.
- Acute severe UC: IV hydrocortisone; assess at day 3; rescue with infliximab or ciclosporin, or colectomy.
Remember Domperidone and methylnaltrexone both work because they stay outside the brain.
Other GI drugs
- Octreotide and terlipressin for variceal bleeding (splanchnic vasoconstriction).
- Ursodeoxycholic acid: primary biliary cholangitis, small cholesterol stones, cholestasis of pregnancy.
- Pancreatic enzymes with meals for exocrine insufficiency; antispasmodics (mebeverine, hyoscine butylbromide, peppermint oil) for IBS; rifaximin for encephalopathy.
How FCPS asks about this
- Why take omeprazole before breakfast: it binds only actively secreting pumps.
- Warfarin INR rises after cimetidine: hepatic CYP450 inhibition.
- Domperidone versus metoclopramide: domperidone barely crosses the BBB, so fewer extrapyramidal effects.
- Loperamide without central effects: P-glycoprotein pumps it out of the brain.
- Low sperm count on sulfasalazine: sulfapyridine; switch to mesalazine.
- Atropine in diphenoxylate tablets: discourages deliberate overdose.
- Hypercalcaemia, alkalosis and AKI with calcium antacids and milk: milk-alkali syndrome.
Test yourself on this topic
5 of the 44 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
Colonoscopy in a 65-year-old woman with long-standing constipation shows dark brown, tiger-striped mucosa. Biopsy shows macrophages laden with brown pigment in the lamina propria. Which of the following laxatives has she most likely been using for years?
Answer: Senna
Melanosis coli is caused by long-term use of anthraquinone stimulant laxatives such as senna and cascara. These drugs cause apoptosis of colonic epithelial cells, and the cell debris is engulfed by macrophages in the lamina propria, forming a lipofuscin-like brown pigment. It is harmless and fades months after stopping the drug. Osmotic and bulk-forming laxatives do not cause it.
Melanosis coli
- Cause: anthraquinone laxatives (senna)
- Epithelial apoptosis, pigment in macrophages
- Brown tiger-striped mucosa
- Benign, reversible
Remember Brown colon: ask about senna.
Exam trap Melanosis coli is not premalignant; it does not need surveillance.
Why the other options are wrong
- Lactulose An osmotic laxative; no pigmentation.
- Ispaghula husk A bulk-forming laxative; no pigmentation.
- Macrogol An osmotic laxative; no pigmentation.
- Docusate A stool softener; no pigmentation.
Which laxative acts as a surfactant, letting water and fat penetrate the stool so that it softens?
Answer: Docusate sodium
Docusate is a stool softener (a detergent or surfactant) and also has a mild stimulant effect. Bulk-forming agents (ispaghula) hold water and add bulk; osmotic agents (lactulose, macrogol) draw water into the bowel; stimulants (senna, bisacodyl) increase motility. For opioid constipation a stimulant plus softener is usual; bulk agents are avoided.
Laxative groups
- Softener: docusate
- Bulk: ispaghula
- Osmotic: lactulose, macrogol
- Stimulant: senna, bisacodyl
Remember Docusate is the soap that softens.
Exam trap Bulk laxatives worsen opioid constipation.
Why the other options are wrong
- Senna Stimulant.
- Lactulose Osmotic.
- Ispaghula husk Bulk-forming.
- Bisacodyl Stimulant.
A man with metastatic lung cancer on regular oral morphine has had no bowel movement for six days despite senna and macrogol. His pain is well controlled and must stay so. Which drug is most appropriate?
Answer: Subcutaneous methylnaltrexone
Opioids slow gut transit through μ receptors in the enteric nervous system, and tolerance to this effect does not develop. Methylnaltrexone is a quaternary μ-opioid antagonist that does not cross the blood–brain barrier, so it blocks gut opioid receptors and relieves constipation without reversing central analgesia or causing withdrawal. Naloxone given IV crosses into the brain and would reverse pain control. It is contraindicated if bowel obstruction is suspected.
Peripheral opioid antagonists
- Opioid constipation: no tolerance
- Methylnaltrexone: quaternary, stays out of the brain
- Relieves gut, keeps analgesia
- Not in bowel obstruction
Remember Block the gut opioid, spare the brain one.
Exam trap Exclude obstruction before giving a peripheral opioid antagonist.
Why the other options are wrong
- Intravenous naloxone Crosses the blood–brain barrier and reverses analgesia.
- Oral loperamide An opioid antidiarrhoeal; would worsen constipation.
- Intravenous metoclopramide A prokinetic, but not effective enough here and does not target opioid receptors.
- Oral codeine Another opioid; worsens constipation.
A woman's UTI fails to respond to oral ciprofloxacin, which she took together with a magnesium–aluminium antacid. What is the most likely reason?
Answer: Chelation reduced ciprofloxacin absorption
Divalent and trivalent cations such as magnesium, aluminium, calcium, iron and zinc form insoluble chelates with fluoroquinolones and tetracyclines in the gut. This sharply reduces absorption, so blood and urine levels may be too low to cure the infection. The antibiotic should be taken at least 2 hours before or 4–6 hours after antacids, iron or milk products. Antacids do not induce liver enzymes.
Antacid chelation
- Mg, Al, Ca, Fe, Zn chelate drugs
- Affects quinolones, tetracyclines
- Also levothyroxine, bisphosphonates
- Separate doses by 2–6 hours
Remember Metals in the gut lock up quinolones.
Exam trap Milk and calcium-fortified drinks cause the same problem as antacids.
Why the other options are wrong
- The antacid induced hepatic metabolism Antacids do not induce CYP450 enzymes.
- Raised gastric pH destroyed the drug Ciprofloxacin is not destroyed by higher gastric pH.
- The antacid increased renal clearance Renal clearance is not the main effect.
- Magnesium antagonised the antibacterial action The problem is absorption, not antagonism at the target.
A 30-year-old man with ulcerative colitis well controlled on sulfasalazine is investigated for infertility, and his semen analysis shows a low sperm count. Which component of the drug is responsible, and what is the remedy?
Answer: Sulfapyridine; switch to mesalazine
Sulfasalazine is 5-aminosalicylic acid (5-ASA) linked by an azo bond to sulfapyridine. Colonic bacteria split the bond, releasing 5-ASA, which acts topically on the colonic mucosa, and sulfapyridine, which is absorbed and causes most adverse effects: reversible oligospermia, rash, headache, haemolysis in G6PD deficiency and agranulocytosis. Switching to mesalazine, a 5-ASA preparation without sulfapyridine, keeps the colitis controlled and the sperm count usually recovers within months.
Sulfasalazine
- = 5-ASA + sulfapyridine (azo bond)
- Split by colonic bacteria
- Sulfapyridine: oligospermia, rash, haemolysis
- Mesalazine avoids sulfapyridine
Remember Sulfa part causes the side effects.
Exam trap The oligospermia is reversible; it is not a reason to stop all treatment.
Why the other options are wrong
- 5-ASA; switch to prednisolone 5-ASA is the active part and does not reduce sperm count.
- Sulfapyridine; add folic acid only Folate helps the folate deficiency, not the oligospermia.
- 5-ASA; switch to olsalazine Olsalazine is two 5-ASA molecules; 5-ASA is not the cause.
- Azo bond; reduce the dose The azo bond is just the carrier link.
Where this sits in the CPSP syllabus
- Paper 1: GI, respiratory and endocrine drugs, Acid-peptic, antiemetic, laxative, IBD and motility drugs
- Medicine & Allied, Paper 2: Systemic drugs, GI drugs: antiemetics, purgatives, antacids, antidiarrhoeals, peptic ulcer drugs
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