Category:Antisecretory agents

An antisecretory agent is a medicine that reduces the secretion of gastric acid by the parietal cell of the stomach. The category covers two principal pharmacological strategies: competitive antagonism at the histamine H2 receptor on the basolateral face of the parietal cell, and irreversible inhibition of the gastric H+/K+-ATPase ("proton pump") at the apical face. A third more recent class, the potassium-competitive acid blockers (P-CABs), inhibits the same pump by a reversible competitive mechanism. The medicines in this category transformed the treatment of peptic ulcer disease, gastroesophageal reflux disease, the Zollinger-Ellison syndrome, and the prevention of gastrointestinal bleeding in critical illness, and largely eliminated the elective surgical management of peptic ulcer that dominated gastroenterology before 1980.

The clinical understanding of acid secretion is older than its pharmacology. In 1822 the trapper Alexis St. Martin was wounded by an accidental shotgun discharge at Fort Mackinac in the Michigan Territory; the army surgeon William Beaumont treated the gunshot, and as St. Martin's stomach healed it left a permanent fistula through the abdominal wall through which Beaumont, over the following decade, conducted some of the most direct observations of gastric function ever made.^[1] The physiology was refined by Ivan Pavlov in St Petersburg, whose work on conditioned and cephalic phases of acid secretion contributed to his 1904 Nobel Prize; and by John Edkins in London, who in 1905 hypothesised an antral hormone he named gastrin that stimulated acid secretion, though the hormone was not chemically identified until Rod Gregory and Hilda Tracy purified it in 1964.

The first specific antisecretory medicine was the second of James Black's receptor antagonists. After his successful development of propranolol at Imperial Chemical Industries in 1964, Black moved to Smith Kline & French in Welwyn with the explicit goal of developing an antagonist at the then-hypothetical second histamine receptor that he believed mediated acid secretion. Existing antihistamines (the H1 antagonists used for allergic conditions) did not inhibit acid secretion; Black reasoned that a different receptor subtype was responsible. Eight years of medicinal chemistry produced burimamide in 1972, metiamide in 1973, and finally cimetidine in 1976, the first clinically useful H2-receptor antagonist.^[2] Black received the Nobel Prize in 1988 for the two receptor-antagonist programmes. Cimetidine had clinically significant interaction liability (inhibition of CYP isoforms including CYP3A4) and central-nervous-system effects (confusion in the elderly, gynaecomastia on long use); ranitidine (Glaxo, 1981), famotidine (Yamanouchi, 1985), and nizatidine (Eli Lilly, 1988) followed with improved profiles. Ranitidine was withdrawn worldwide between 2019 and 2020 after the discovery of carcinogenic N-nitrosodimethylamine impurities formed during storage.

The next pharmacological generation came from Sweden. In the early 1970s the Astra research programme, led by Ivan Östholm and the medicinal chemist Per Lindberg, set out to inhibit acid secretion not at the histamine receptor but at the terminal proton-pumping enzyme of the parietal cell. The chemistry was unconventional. The lead compound, picoprazole, was a benzimidazole with no acid-suppressive activity in vitro; in the acidic environment of the parietal-cell secretory canaliculus, however, it underwent intramolecular rearrangement to a sulfenamide that covalently bound a cysteine residue of the H+/K+-ATPase, irreversibly inactivating the enzyme.^[3] Optimisation produced omeprazole (Losec, Astra, approved in 1988), the first proton pump inhibitor and the first medicine of any class to reliably heal peptic ulcer and to suppress reflux symptoms to near-complete remission. Omeprazole was followed by pantoprazole (Byk Gulden, 1994), lansoprazole (Takeda, 1995), rabeprazole (Eisai, 1999), and the (S)-enantiomer esomeprazole (AstraZeneca, 2001). The Australian gastroenterologists Barry Marshall and Robin Warren had, between 1982 and 1984, shown that most peptic ulcer disease was caused by infection with the spiral organism Helicobacter pylori and was curable with antibiotic eradication therapy combined with a PPI; Marshall famously demonstrated causation by drinking a broth of the organism himself, developing gastritis, and curing it with bismuth and metronidazole. They received the Nobel Prize in 2005, and the combination of PPI with two antibiotics has been the standard H. pylori eradication regimen since.^[4]

The contemporary clinical position of the antisecretory agent is, perhaps paradoxically, one of restraint. The proton pump inhibitors are among the most widely prescribed medicines in the developed world; one in eight American adults takes one regularly. A growing body of observational evidence has associated long-term PPI use with vitamin B12 and magnesium deficiency, with osteoporotic fracture, with Clostridioides difficile infection, with community-acquired pneumonia, and (less consistently) with chronic kidney disease and dementia. Most of these associations remain disputed and the controlled-trial evidence for harm is small, but the recognition that PPIs are often continued indefinitely without ongoing indication has motivated deprescribing initiatives. The most recent pharmacological addition, the potassium-competitive acid blocker vonoprazan (Takeda, 2014 in Japan, 2022 in the United States), is reversibly competitive at the K+-binding site of the H+/K+-ATPase and produces faster, more complete, and longer-duration acid suppression than the PPIs without the requirement for activation by acid; whether vonoprazan will displace the PPI class or supplement it remains to be seen.

The other antisecretory medicines fill specific niches. The somatostatin analogue octreotide suppresses gastrin and other gut-hormone secretion in carcinoid and the Zollinger-Ellison syndrome; sucralfate, an aluminium-sucrose complex, coats the ulcer base rather than suppressing acid; the antimuscarinic pirenzepine, formerly used for its M1-selective inhibition of cholinergically driven acid secretion, has been largely retired. The aluminium-, magnesium-, and calcium-containing antacids (Maalox, Mylanta, Tums) neutralise rather than reduce acid secretion and remain in over-the-counter use for occasional symptom relief.

By mechanism:

• Proton pump inhibitors (irreversible covalent inhibition of the gastric H+/K+-ATPase): omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole, rabeprazole
• H2-receptor antagonists (competitive inhibition at the parietal-cell histamine H2 receptor): famotidine, cimetidine (still available but rarely prescribed because of interaction profile), nizatidine
• Potassium-competitive acid blockers: vonoprazan (Japan and the U.S.)
• Mucosal protectants (act on the ulcer rather than the acid): sucralfate, bismuth compounds
• Somatostatin analogues: octreotide, lanreotide (for gastrinoma and carcinoid)
• M1-selective antimuscarinics (largely retired): pirenzepine, telenzepine

The boundary of this category is "medicine that reduces gastric acid secretion." The antacids (sodium bicarbonate, aluminium hydroxide, magnesium hydroxide, calcium carbonate) neutralise acid that has already been secreted; they are listed under antacids but not here. The medicines used in functional dyspepsia and the prokinetics for gastroparesis (prokinetics including metoclopramide, domperidone, prucalopride) act on motility rather than secretion and are listed under their own category. The medicines for inflammatory bowel disease (the 5-aminosalicylates, the biologics) are not antisecretory agents and are listed separately.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.