Hydrogen receptor antagonists are drugs that were developed to decrease the production of stomach acid, in other words as a modern acid reflux treatment. They work by blocking the action of histamine on parietal cells in the stomach. Although extremely popular and successful, and widely used in the 1980s and 90s for the treatment of heartburn symptoms and dyspepsia, they have been supplanted by proton pump inhibitors.
The safety of these drugs in treating acid reflux is recognized in the fact that the most common members of this group of medications – namely cimetidine, ranitidine, famotidine, and nizatidine – are all available over-the-counter without a prescription.
The first drug to be developed in this group was cimetidine, which is marketed as Tagamet. Its development can be traced back to the fact that as long ago as 1964 scientists recognized that histamine stimulates the production of stomach acid. However, they also knew that traditional antihistamines do not affect stomach acid production. This led scientists to the conclusion that there were two types of histamine receptors, and if they were able to identify the one in the stomach, they would be able to produce a compound that inhibited its action.
By analyzing the structure of histamine, and manufacturing hundreds of compounds to try and identify antagonists of the unknown hydrogen receptor in the stomach, they were able to eventually manufacture cimetidine. This proved to be a breakthrough in the medical treatment of the symptoms of acid reflux. Subsequently, another company refined the structure of the compound and in doing so produced ranitidine, which was marketed as Zantac. This product was found to be more powerful and have a longer-lasting effect. By 1988 it was actually the world’s largest-selling prescription drug. A most effective remedy for acid reflux it was, too, as my story indicates.
These drugs work by competing with histamine for the parietal cell hydrogen receptor; firmly attached to this, they block the secretion of acid. This has proved incredibly effective in treating peptic ulcers, gastroesophageal reflux disease, and dyspepsia.
For those who suffered – and still do – from stomach problems caused by stress, the introduction of these hydrogen blockers was a radical and immensely transformative experience. They’re still extremely useful for people who are looking for a heartburn remedy and are much more effective at suppressing the symptoms of acid reflux than simple antacids, whose effect is limited and the duration of which tends to be rather short. Cimetidine proved to have a number of side effects, which led to the other products becoming more popular.
These drugs are being replaced by proton pump inhibitors, which have now become the preferred treatment for heartburn, GERD, and esophagitis, due to the fact that they promote healing rather better than hydrogen antagonists.
Proton Pump Inhibitors
Proton pump inhibitors work by blocking the action of hydrogen potassium ATPase which then inhibits gastric acid production. They are now the medication of choice for acid reflux treatment and the cure of gastroesophageal reflux disease and peptic ulcer.
The final step in acid production is clearly the one that is most beneficial to “attack”. The action of the proton pump in the secretory membrane of the parietal cell was known to fulfill this requirement; using newly discovered compounds known as benzimidazoles allowed scientists to develop refined products such as omeprazole which effectively stopped the production of acid in the stomach.
These compounds have a sophisticated mechanism of action, but basically, they target the last step in acid production, which is therefore independent of the stimulus to acid secretion, and they also bind to the enzyme, which makes their effect long-lasting.
Naturally enough, this work continues: the development of more sophisticated ways of treating acid reflux is the goal. Although PPIs share some common molecular structural features, the fact that they have different chemical formulae results in different levels of effectiveness, activation at different levels of pH, and speeds of metabolization by the liver.
They have “revolutionized” treatment of acid reflux, but a new class of drugs is now under development — the potassium competitive acid blockers will acid pump antagonists.
Regrettably, proton pump inhibitors do produce an elevated chance of the development of food allergies because of the presence of undigested proteins in the stomach which then pass into the small intestine. This leads to the possibility of sensitization to proteins and allergic reactions, but it’s unclear whether this is a consequence of long-term use only.
In general, they have few side effects, but those which do occur include headache, nausea, abdominal pain, and some more subtle effects such as decreased vitamin B12 absorption. The use of these drugs is also associated with an increased risk of acquiring pneumonia, skin aging, and Clostridium difficile infection.
Furthermore, long-term treatment of acid reflux with PPIs seems to produce an increase in the likelihood of fracture of the hip, wrist, and spine of people aged 50 or older. This seems to be because these drugs interfere with the bone production mechanism of the bone producing cells osteoclasts.
And discontinuation of the prescription seems to produce a rebound effect whereby gastric symptoms are temporarily increased – although this is a short-term effect, it can be a problem.