Describe the physiology of gastric acid secretion. Classify the drugs used in peptic ulcer and reflux disease with their uses and adverse effects.

Physiology of Acid Secretion and Drug Targets

Three stimuli act on the parietal cell → gastrin (from G cells) → CCK2 receptor; acetylcholine (vagal) → M3 receptor; histamine (from ECL cells) → H2 receptor → Gastrin and acetylcholine act largely by releasing histamine from ECL cells, so histamine is the final common mediator → Histamine → H2 → cAMP rises → All three converge on the H+/K+ ATPase — the proton pump on the canalicular membrane → Acid secretion

• The pump is the final step, so a proton pump inhibitor blocks acid production whatever the stimulus; an H2 blocker only removes the histamine contribution. This single anatomical fact explains why proton pump inhibitors are so much more effective
• Mucosal defence — mucus and bicarbonate layer, epithelial renewal, and mucosal blood flow, all maintained by prostaglandin E2. Ulceration results from an imbalance between aggression and defence

Classification of Antiulcer Drugs

Proton Pump Inhibitors in Detail

• They are prodrugs — weak bases that concentrate in the acidic canaliculus of the parietal cell, where they are converted to a sulphenamide that binds irreversibly to cysteine residues on the pump
• Because the binding is irreversible, the effect outlasts the drug — the plasma half-life is 1 to 2 hours but acid suppression lasts 24 to 48 hours, until new pumps are synthesised
• Must be taken 30 to 60 minutes before a meal — they only inhibit actively secreting pumps, and the meal is what activates them. Taken with or after food, or on an empty stomach with no meal to follow, much of the dose is wasted. This is the commonest reason a proton pump inhibitor "does not work"
• Acid-labile, so they are given as enteric-coated granules

Uses

• Peptic ulcer — gastric and duodenal, with H. Pylori eradication where present
• Gastro-oesophageal reflux disease and erosive oesophagitis — the most effective treatment
• NSAID-associated ulcer — treatment and prophylaxis
• Zollinger-ellison syndrome — high doses
• Upper gastrointestinal bleeding — high-dose intravenous infusion after endoscopic therapy, since clot stability requires a pH above 6
• Stress ulcer prophylaxis in critically ill patients with defined risk factors
• Functional dyspepsia and Barrett oesophagus

Adverse Effects and Interactions

• Common and minor — headache, nausea, abdominal pain, diarrhoea, flatulence, rash
• From long-term acid suppression — hypomagnesaemia (which causes hypocalcaemia and hypokalaemia resistant to replacement until magnesium is corrected), vitamin B12 and iron malabsorption (both need acid), and reduced calcium absorption
• Infection — acid is a barrier, so its removal increases clostridioides difficile colitis, other enteric infections and community-acquired pneumonia
• Bone — an association with hip and vertebral fracture on long-term use
• Renal — acute interstitial nephritis, and an association with chronic kidney disease
• Rebound acid hypersecretion on stopping after prolonged use, from gastrin-driven ECL cell hyperplasia — symptoms recur, the patient concludes they still need the drug, and the prescription becomes permanent
• Interactions — omeprazole inhibits CYP2C19 and reduces activation of clopidogrel (a prodrug), so pantoprazole is preferred in patients on clopidogrel. All reduce absorption of drugs needing acid — ketoconazole, itraconazole, atazanavir, iron

Helicobacter Pylori Eradication

• Present in most duodenal and many gastric ulcers, and classed as a class I carcinogen for gastric adenocarcinoma and malt lymphoma
• Eradication reduces ulcer recurrence from about 80% a year to under 5% — it converts a chronic relapsing disease into a cured one
• Standard triple therapy — a proton pump inhibitor with clarithromycin and amoxicillin for 14 days
• Bismuth quadruple therapy — proton pump inhibitor, bismuth, metronidazole and tetracycline — is preferred where clarithromycin resistance exceeds 15%, which includes much of India
• The acid suppressant is an essential antibacterial adjuvant, not merely symptomatic: amoxicillin and clarithromycin are unstable and less active at low pH, so raising the gastric pH is what allows them to work
• Confirm eradication at least 4 weeks after treatment by urea breath or stool antigen test, having stopped the proton pump inhibitor 2 weeks beforehand to avoid a false negative

Applied Aspects

• Ask when the patient takes the tablet before concluding a proton pump inhibitor has failed — before breakfast, not at bedtime or with food
• Test and treat H. Pylori in any patient with a proven ulcer, and in young patients with dyspepsia without alarm features; do not simply suppress acid indefinitely
• Review long-term prescriptions — a very large proportion of patients on lifelong proton pump inhibitors have no continuing indication, having been started during an admission and never stopped
• Withdraw gradually after prolonged use, or rebound symptoms will convince both patient and doctor that the drug is still needed
• Investigate alarm features rather than treating empirically — weight loss, dysphagia, vomiting, anaemia, bleeding, a mass, or new dyspepsia over 50; these need endoscopy
• Gastric cancer is common in parts of India and empirical acid suppression can mask it for months; the threshold for endoscopy should be low
• Sucralfate must not be given with an acid suppressant, since it requires acid to polymerise; and it binds other drugs, so doses must be separated
• Antacids interfere with the absorption of many drugs — fluoroquinolones, tetracyclines, iron, levothyroxine, bisphosphonates — and should be separated by at least 2 hours
• Aluminium-containing antacids accumulate in renal failure, and magnesium-containing ones cause hypermagnesaemia; both are avoided in advanced kidney disease
• NSAID use is the other major cause of ulceration, and in a patient with an ulcer the NSAID history matters as much as the H. Pylori status; both must be addressed or the ulcer returns
• H2 blockers still have a place — for nocturnal acid breakthrough alongside a proton pump inhibitor, and where the latter is contraindicated; famotidine has replaced ranitidine
• Cimetidine should be avoided in patients on warfarin, phenytoin or theophylline, and in men, given its enzyme inhibition and antiandrogen effects
• Lifestyle measures help in reflux — weight loss, raising the head of the bed, avoiding late meals, alcohol and smoking; they are cheap and are usually omitted in favour of a prescription
• Misoprostol prevents NSAID ulcers but is abortifacient, and must not be given to a woman who could become pregnant