Sites of action of drugs reducing gastric acidity
H2 receptor antagonists
Examples – cimetidine, famotidine, nizatidine, ranitidine
Histamine has two primary effects on the gastrointestinal tract, mediated by H1 and H2 receptors. H1 agonism causes contraction of gut smooth muscle, whereas H2 agonism causes secretion of gastric acid. The H2 antagonists typically resemble the imidazole-ring end of histamine and are hydrophilic. The H2 antagonists are reversible competitive antagonists which each feature a five-membered ring similar to the imidazole of histamine, with a specific structure as follows:
Cimetidine – imidazole ring
Famotidine – guanidinothiazole ring
Nizatidine – thiazole ring
Ranitidine – furan ring
H2 antagonism inhibits both basal levels and stimulated release of gastric acid. Pepsin secretion is reduced in line with the decrease in gastric volume even though secretion of pepsin is mediated by acetylcholine. As pepsin is usually secreted in excess of requirements, this does not present a problem. H2 receptors are also present in the uterus, heart, blood vessels, ductus arteriosus and the lower oesophageal sphincter. Clinically, the H2 antagonists have little effect on these other tissues, and there are no clinical applications related to these sites.
Cimetidine
Cimetidine is an H2 antagonist with slight antiandrogenic effect that may cause gynaecomastia and impotence. Peak effect is achieved 80 minutes after oral administration, and the terminal half-life is 2 hours. It is given twice daily, is metabolised in the liver and binds to cytochrome P450, causing inhibition. It also reduces hepatic blood flow. Seventy per cent of cimetidine is excreted unchanged in the urine. T lymphocytes have H2 receptors, and blockade of these may inhibit suppressor T-cell function, resulting in enhanced immune system activity. This effect may be harmful in the presence of autoimmune conditions or after organ transplantation. H2 receptors in the atria are responsible for atrial rhythmicity, and cimetidine may cause bradydysrhythmias, especially when given intravenously.
Famotidine
Famotidine is an H2 antagonist that may be intravenously administered twice daily. It reduces acid and pepsin content, reduces gastric volume, and is about 50 times more potent than cimetidine. It is excreted in the urine, having a half-life of 3 hours and a duration of action of 10 hours. Cytochrome P450 is unaffected.
Nizatidine
Nizatidine is currently the H2 antagonist with the shortest half-life (1.3 hours). It may be given orally or intravenously. It does not affect cytochrome P450. In high doses, nizatidine may increase salicylate absorption. Nizatidine also causes non-competitive inhibition of acetylcholinesterase similar to that caused by neostigmine, and so possesses prokinetic activity too.
Ranitidine
Ranitidine has a peak effect 100 minutes after oral administration, and the terminal half-life is 2.5 hours. There is a substantial first-pass effect that is avoided by use of the intravenous preparation. It is metabolised in the liver and binds to cytochrome P450, causing inhibition, but this effect is only about one-tenth that of cimetidine and thus rarely achieves clinical significance.
Proton pump inhibitors
Examples – esomeprazole, lansoprazole, omeprazole, pantoprazole, tenatoprazole
The proton pump inhibitors (PPIs) directly affect the acid-secreting pump of the gastric parietal cells, in effect bypassing the muscarinic, gastrin and H2 receptors. Available proton pump inhibitors are substituted benzimidazoles (imidazole and benzene ring together) joined to a pyridine ring by a sulphenyl group. PPIs are weak bases (high pKa) and are administered orally in buffered capsules to minimise the effects of gastric acid before arrival at the site of action. This allows slow release and gradual absorption of the dose. They are readily absorbed in this non-ionised form. They are prodrugs and are activated by exposure to acid conditions (pH 0.8–1.0) in the gastric parietal-cell canaliculi on the luminal surface of the stomach. This causes protonation of one nitrogen atom of the imidazole ring and that of the pyridine ring, which are therefore ionised. The two additional hydrogen ions (protons) then join with the oxygen on the sulphur atom to release water, and in doing so another ring is formed. The end result is a planar tetracyclic sulphonamide which is the active form of the PPI. The active form accumulates within the parietal canaliculi near the luminal surface and binds to the target enzyme. The sulphur of the PPI combines covalently with sulphydryl groups of cysteine amino acid residues in the H+K+ATPase pump and so prevents hydrogen ion passage. These inhibitors are therefore very selective. The PPIs are strongly bound to the pump enzyme, and so the effect of these drugs is much longer than the elimination half-lives would suggest.
Omeprazole
The structure of omeprazole constitutes substituted benzimidazole and pyridine rings joined by a sulphoxide link. It is a prodrug, converted within the parietal cell to sulphenamide, the active form. It has a highly selective effect that increases over several days to a plateau, probably because the reduced gastric acid reduces its degradation and increases bioavailability. Plasma distribution half-life is only 3 minutes, but gradual absorption and accumulation in the parietal cells results in a prolonged therapeutic effect. There is minimal crossing of the blood–brain barrier but free crossing of the placenta. Omeprazole undergoes hepatic metabolism. Untoward effects are limited, although long-term use may result in hypergastrinaemia, thought to be of little consequence. Cytochrome P450 is inhibited, leading to a prolonged half-life of benzodiazepines and phenytoin as well as other agents sharing this elimination pathway.
Lansoprazole and pantoprazole, second-generation agents, are similar in structure to omeprazole. Both achieve higher bioavailability (lansoprazole 85% and pantoprazole 75%). Gradual absorption and accumulation in the parietal cells results in a prolonged therapeutic effect. The drug is conjugated in the liver and excreted in the urine (80%) and faeces.
Lansoprazole has a still higher bioavailability (85%), elimination half-life 0.9 hours (clearance 31 L h–1, volume of distribution 29 litres, 50% excreted in urine). Unchanged drug is eliminated by the biliary route.
Rabeprazole binds more rapidly to the proton pump than the other PPIs, and also dissociates more easily.
Prostaglandins
Example – misoprostol
Prostaglandins E2 and I2 (PGE2, PGI2) inhibit gastric acid secretion and stimulate the production of mucus and bicarbonate, and therefore have a protective effect on the gastric mucosa. Natural prostaglandins are rapidly eliminated, and synthetic analogues have therefore been developed.
Misoprostol is a synthetic prostaglandin E2 analogue that reduces gastric acid secretion and antagonises the antiprostaglandin effects of the NSAIDs. It is most useful when these are a factor in the causation of ulcer formation, and it can be used in conjunction with NSAIDs (to prevent further ulceration) when alternatives to NSAIDs are unacceptable. The only untoward effect of note is the occurrence of diarrhoea.
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