Histamine H2-receptor antagonists and proton pump inhibitors are the main classes of drug used to inhibit gastric acid secretion. The former act by reversibly blocking the action of histamine, which is released from other mucosal cells in anticipation of a meal or when food enters the stomach. The proton pump inhibitors have a long-lasting effect on acid secretion. They inactivate the final step in acid secretion - the transport of hydrogen ions from the parietal cells to the lumen of the gastric glands.
Safe and effective inhibition of gastric acid secretion has been a long-desired goal of clinicians who treat acid-related diseases such as gastro-oesophageal reflux disease and peptic ulcer. Nowadays, two classes of drug - the histamine H2-receptor antagonists and the proton pump inhibitors (PPI) - achieve this goal with a high level of success.
The pharmacodynamics of the PPIs are easier to grasp because they block the final step in acid secretion. To understand the effects of H2-receptor antagonists requires some knowledge of the signalling pathways that lead to acid secretion.
When acid secretion is stimulated with histamine, the systemic adverse effects of histamine can be prevented by a conventional antihistamine drug without affecting acid secretion. This suggests the existence of two classes of histamine receptors, one mediating acid secretion (H2-receptors) and the other mediating all other effects of histamine (H1-receptors).
Histamine H2-receptors are located on the basolateral membranes of the acid-secreting parietal cells in the stomach. They are activated by histamine derived from neighbouring mucosal cells. We now believe the main source of this histamine to be the principal endocrine cell of the gastric body or corpus - the enterochromaffin-like (ECL) cell. The ECL cells are mainly located in the lower part of the gastric glands, well-positioned to deliver their histamine into the capillaries which flow past them and the parietal cells (Fig. 1).
The ECL cells have receptors on their cell membranes for the peptide hormone gastrin, and a neurotransmitter released in response to vagal stimulation. The parietal cell basal membrane carries receptors for histamine (H2), gastrin and acetylcholine. We used to believe that the gastrin and acetylcholine receptors on the parietal cell were particularly important in acid secretion. However, current evidence suggests that the gastrin receptors on the parietal cell are more concerned with cell growth than signalling for acid secretion. The high affinity gastrin receptors that activate acid secretion are actually the receptors on the ECL cells.
The main messages that tell the stomach to secrete acid after a meal are the release of gastrin and acetylcholine. These messages are channelled via the ECL cells which then release histamine. Histamine then stimulates the parietal cells to secrete acid.
Once the histamine H2-receptors on the parietal cell are activated, acid secretion is started via intracellular cyclic AMP. This in turn activates the acid transporter (H+/K+-ATPase) on the luminal side of the parietal cell. These proton pumps are stored in intracellular tubules and vesicles, and are rapidly inserted into the cell membrane - the invaginated secretory canaliculus (Fig. 1) - so they can transport hydrogen ions out of the cell and into the gastric glands.
In Australia, the available drugs are cimetidine, ranitidine, famotidine and nizatidine. Their pharmacological properties are much more similar than they are different. All are competitive inhibitors of the histamine H2-receptor on parietal cells. Their duration of action mirrors their plasma elimination half-lives, and is measured in a few hours. Large doses can produce marked inhibition of basal or stimulated acid secretion, although the effect disappears quickly. This is true whether the acid secretion is stimulated physiologically by eating (mediated by gastrin and cholinergic pathways), or the sight, smell or taste of food (vagal pathways, gastrin); or experimentally by infusion of histamine, gastrin or acetylcholine.
As the drugs have a relatively short duration of action, they are normally given twice daily for reflux disease or healing gastric ulcers. For healing duodenal ulcers, giving the full daily dose in the evening is as effective as dividing the dose into two. Nowadays, however, the main priority for healing ulcers is treating Helicobacter pylori if the organism is present.
Standard doses of H2-receptor antagonists usually elevate intragastric pH by about one unit, averaged over 24 hours. This is only a modest elevation compared with that achievable with proton pump inhibitors, but nevertheless is often sufficient for successful treatment.
One interesting feature of blockade of the parietal cell H2-receptor is that tolerance develops after a few days of dosing. As a result, the degree of inhibition reduces, often by half. This is usually not a clinical problem, although it may be one reason why H2-receptor antagonists are less successful than PPIs for the treatment of severe reflux disease. This tolerance does become a major problem for patients with massive hyper secretion of acid - as in the Zollinger-Ellison syndrome. Tolerance becomes a limiting factor and the control of acid secretion usually fails after some weeks of treatment. In this rare disease, control of acid secretion with a PPI should be the normal approach.
This class of compound is generally very well tolerated. Histamine H2-receptors are present in other tissues, e.g. the heart and the brain. However, in clinical practice it is unusual for patients to be aware of any adverse effects from these drugs. Prescribers need to be aware that H2-receptor antagonists (especially cimetidine) may interfere with the metabolism of some other drugs.
Proton pump inhibitors
This newer class of drugs includes omeprazole, lansoprazole and pantoprazole. All these drugs substantially inhibit acid secretion. Their chemical structures differ only minimally, and for practical purposes their pharmacology is identical.
Omeprazole was developed by a Swedish research group during a search for a drug that might inhibit the release of gastrin from the gastric mucosa. However, it soon became apparent that omeprazole was inhibiting the newly discovered acid pump on the surface membrane of the acid-secreting cell (Fig. 1).
The PPIs are effectively pro-drugs. They are converted into an active form by a high acid concentration, e.g. omeprazole becomes a sulfenamide. In the gastric lumen this activation by acid is a problem. The sulfenamide is a short-lived compound and cannot reach the acid pump on the parietal cell membranes by diffusing the long distance from the stomach lumen down into the pits and glands of the mucosa. For this reason, the PPI needs an enteric-coated form so that most of it can survive the passage through the stomach. It is then released in the small intestine where it is absorbed and travels to the parietal cells in the stomach via the circulation. The diffusion distances are then very short (micrometres) and the PPI is converted to its active form as soon as it reaches the acid space just outside the acid pump itself. It is then perfectly positioned to bind covalently to the H+/K+-ATPase on the parietal cell membrane. This binding is long lasting but is overcome by the synthesis of new pump molecules. Since the average half-life of the pump molecules is about 24 hours, this is the average half-time for the suppression of acid secretion.
Although the plasma half-lives of PPIs are quite short, their mechanism of action enables most patients to be satisfactorily treated with once-daily dosing. Generally it does not matter whether the dose is given in the morning or the evening. However, acid secretion recovers faster in some patients than others and it may be worth experimenting with switching the dose to the evening. This may benefit patients with reflux whose nocturnal symptoms are not relieved when the PPI is given in the morning. About 10-20% of patients with severe reflux disease will get better relief of symptoms with a twice-daily dose.
PPIs elevate intragastric pH much more readily than H2-receptor antagonists. In untreated individuals, median 24 hour pH in the gastric lumen is about 1.5. This increases to about 2.5 with an H2-receptor antagonist while PPIs in standard dosage can usually increase the median pH to about 4-5. This is of particular value when treating resistant gastro-oesophageal reflux disease. This elevation of pH also seems to be an advantage when acid suppression is used as part of the triple therapy strategies for treating H. pylori infection.1
One interesting property of the current generation PPIs is that their effects can be a little more unpredictable when the dosage is lowered. For example, one study with omeprazole showed that a 10 mg dose once daily had little effect on 24 hour median pH in three of eight volunteers while several of the remainder had marked acid suppression. This phenomenon may be explained by variability in the rate of regeneration of acid pump molecules.
The PPIs are extremely well tolerated. In the trials that established their efficacy, the adverse events reported by patients taking the drugs were usually not statistically different from those of placebo. This presumably relates to the very specific drug delivery and the very tissue-specific localisation of this particular hydrogen/potassium pump.
Initial concerns about potential risks from long-term acid suppression in humans seem to be unfounded. A slightly increased risk of some enteric infections (mainly C. jejuni) has been observed. Data accumulated over the first decade of use do not raise any significant concerns about neoplastic potential in humans. If there are any long-term risks, they are likely to be outweighed by the risks of not treating troublesome acid-related diseases adequately.2
H2-receptor antagonists appear to be a mature family of drugs, with further improvements probably unlikely. Blockade of the proton pump is still evolving, through the development of variants with even more predictable effects, as well as inhibitors that are shorter or longer acting than those currently marketed.
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