Mechanism of action: Since the proton pump (H⁺/K⁺-ATPase) is the final common pathway for acid secretion in gastric parietal cells, inhibition of the pump almost completely blocks acid secretion (Fig. 33.1). Proton pump inhibitors are irreversible inhibitors of H⁺/K⁺-ATPase and the return of acid secretion is dependent on the synthesis of new proton pumps. Proton pump inhibitors are weak bases that are selectively concentrated from the circulation into the acid environment of the secretory canaliculi of the gastric parietal cell. The drugs are then protonated and structurally transform into active derivatives that covalently bind to and irreversibly inhibit the proton pump. Because protonation to the active derivatives only takes place at acid pH, these drugs have a selective action on gastric cells, and proton pumps elsewhere in the body are not inhibited. Acid production is inhibited by about 90% for approximately 24 h following a single dose.

Pharmacokinetics: Proton pump inhibitors are prodrugs that are unstable in acid. They are given orally as enteric-coated formulations; esomeprazole, omeprazole and pantoprazole are also available as intravenous formulations. Elimination is by hepatic metabolism. They have short plasma half-lives (1–2 h) but, because of the irreversible mechanism of action, these bear no relationship to the long biological duration of action. Esomeprazole is the S-isomer of omeprazole that has lower clearance and therefore achieves slightly higher plasma concentrations.

Unwanted effects:

 Gastrointestinal upset, such as nausea, vomiting, abdominal pain, diarrhoea, constipation.

 Headache.

 Omeprazole and esomeprazole are inhibitors of CYP2C9 and CYP2C19 in the liver. This can give rise to drug interactions with other substrates of these isoenzymes, for example decreasing the metabolism and increasing the clinical effects of warfarin, phenytoin and several antiviral drugs (see Table 2.7).

Concerns that substantial reductions of gastric acid, and the associated rise in gastrin secretion, might increase the risk of gastric cancer (comparable to the increased risk in pernicious anaemia) appear to be unfounded. These drugs do not completely abolish acid secretion and intragastric pH can still fall below 4 during part of the day, the critical pH below which bacterial populations that predispose to cancer are thought not to become established. However, symptomatic improvement following treatment with a proton pump inhibitor can mask the symptoms of gastric cancer.

Mechanism of action: Histamine H₂ receptor antagonists act competitively at receptors on gastric parietal cells. They reduce basal acid secretion and pepsin production, and prevent the increase in secretion that occurs in response to several secretory stimuli. Overall, acid secretion is reduced by about 60% (Fig. 33.1).

Pharmacokinetics: Absorption of cimetidine and ranitidine from the gut is almost complete but both undergo limited first-pass metabolism. The drugs are mainly eliminated unchanged by the kidney, in part through active tubular transport. Their half-lives are between 1 and 4 h.

Unwanted effects:

 Diarrhoea and other gastrointestinal disturbances.

 Headache, dizziness, tiredness.

 Rash.

 Drug interactions: cimetidine is an inhibitor of hepatic P450 isoenzymes (see Table 2.7) and can increase the plasma concentrations and actions of drugs such as warfarin, phenytoin and theophylline.

Mechanism of action: Sucralfate is a complex of aluminium hydroxide and sucrose octasulphate. It dissociates in the acid environment of the stomach to its anionic form, which binds to the ulcer base. This creates a protective barrier to pepsin and bile and inhibits the diffusion of gastric acid. Sucralfate also stimulates the gastric secretion of bicarbonate and prostaglandins.

Pharmacokinetics: Sucralfate is only slightly absorbed from the gut (<2%).

Unwanted effects:

 Constipation.

 Bezoar formation (a mass trapped in the gut, usually the stomach), especially if gastric emptying is delayed.

Mechanism of action: Bismuth salts precipitate in the acid environment of the stomach and then bind to glycoprotein on the base of an ulcer. The resulting complex adheres to the ulcer and has similar local effects to sucralfate. Bismuth salts, in combination with antibiotics, were the first effective anti-Helicobacter agents and this effect may have accounted for their ulcer-healing properties. They have now largely been superseded by proton pump inhibitor combinations for this purpose; however, when triple therapy with two antibacterials and a proton pump inhibitor fails, bismuth is included as part of the treatment regimen (see below).

Pharmacokinetics: Bismuth compounds are poorly soluble and only slightly absorbed from the gut.

Unwanted effects:

 Blackened stools and darkened tongue.

Mechanism of action: Misoprostol is an analogue of PGE₁ and has several actions that protect the gastric and duodenal mucosae (see Ch. 29). Misoprostol limits the damage to superficial mucosal cells caused by agents such as acid and alcohol. It is most widely used to prevent NSAID-associated ulcers, and is available in combination products with diclofenac or naproxen (Ch. 29).