Current Treatment

6.27.5.1 Antacids

The earliest drugs used to combat gastric acid were antacids such as chalk (CaCO3) or baking soda (NaHCO3), used by the ancient Greeks. The problem with these drugs was that they only elevated the luminal gastric pH, and did not affect the pH of the gastric epithelium, and, given the capacity of the stomach to secrete 1.5 l of 1 N HCl per day, had to be taken very frequently. With the dawn of modern medical practice in the nineteenth century, use of these agents was combined with bed rest and a bland diet. These measures were largely ineffective when more serious consequences such as perforation or hemorrhage occurred.18 Nevertheless, antacids continue to be used for symptomatic relief, and public awareness has significantly increased in the western world as to the need for medical treatment for frequent upper GI tract symptoms.

6.27.5.2 Anticholinergic Agents

Long before the mechanisms of activation of acid secretion by the stomach were recognized, extract of belladonna was found to ameliorate peptic ulcer symptoms. However, the active ingredient, atropine, has a generalized effect on all the muscarinic receptors in the body, resulting in side effects, such as blurred vision, dry mouth, and urinary tract dysfunction that resulted in abstinence from the drug. Even though atropine was later replaced by more selective M1 receptor antagonists (e.g., pirenzepine), the general muscarinic side effects, although reduced compared with atropine remained.19

6.27.5.3 H2 Receptor Antagonists

Histamine (Figure 1) was discovered by Dale, but a pupil of Pavlov, Piopielski, first described the stimulation of gastric acid secretion. There was much argument whether histamine or gastrin was the major direct stimulant of the parietal cell. In the 1950s, a series of histamine antagonists was synthesized, where the imidazole ring of histamine was modified to other aromatic structures by Bovet and co-workers.20 These antagonists blocked the peripheral actions of histamine, such as vasodilation and mucus secretion, but had relatively little effect on acid secretion. It was therefore suggested that the histamine receptor in the stomach was a different subtype, a putative H2 receptor, as contrasted to the H1 receptor that was blocked by the compounds synthesized by Bovet. In 1963, Black began work on the synthesis and evaluation of compounds able to selectively block the H2 receptor. By modifying the side chain rather than the imidazole ring of histamine. The first H2 receptor antagonist, burimamide, was synthesized in 1970, rapidly followed by metiamide and cimetidine (Figure 1).1'14 The last was the first H2 receptor antagonist in 1977, marketed as Tagamet. Ranitidine, famotidine, and nizatidine were second-generation H2 receptor antagonists where the imidazole ring was no longer retained (Figure 1). These all contained a protonatable nitrogen atom at the end of the side chain, and presumably bound to the receptor as cations.

The H2 receptor antagonists effectively abolished gastrin-stimulated acid secretion, but were less effective against cholinergically stimulated acid secretion.14 This resolved the issue as to whether histamine acting at H2 receptors or gastrin was the primary stimulant of acid secretion. It is now accepted that the action of gastrin on acid secretion is due to stimulation of histamine release from the ECL cell, and is not due to a direct action of this hormone on the parietal cell.21 The efficacy of H2 receptor antagonists relies on their plasma half-life, as these are reversible inhibitors. Further, they are all inverse agonists, able to inhibit the receptor even in the absence of histamine. There were attempts to develop noncompetitive H2 receptor antagonists (e.g., loxitidine),22 but unexpected toxicity terminated their

6.27.5.4 Proton Pump Inhibitors

PPIs were introduced in 1989, the culmination of serendipity and drug design. It is probably correct to state that without the serendipity, the PPIs would never have been designed. Hassle AB in Sweden had for some years a program for the discovery of anti-ulcer drugs using the classic rat ulcer model and measurement of acid secretion. Pyridinyl-2-ethylamide was found to inhibit acid secretion. Modification to pyridinyl-2-ethylthioamide maintained inhibition of acid secretion, but the mechanism was unknown, and remains so. With the discovery of cimetidine, there was speculation that pyridinyl-2-ethylamide might be an H2 receptor antagonist. 2-(Pyridinylmethylthio)benzimidazole was made, and then modified to generate 2-(pyridinylmethylsulfinyl) benzimidazole (timoprazole; Figure 2) to development.

Figure 1 The structure of histamine, cimetidine, ranitidine, and famotidine, showing the retention of the imidazole structure in cimetidine, replaced by a furan ring in ranitidine and a thiazole ring in famotidine.

NCN Cimetidine

Histamine

Ranitidine

Famotidine

Figure 1 The structure of histamine, cimetidine, ranitidine, and famotidine, showing the retention of the imidazole structure in cimetidine, replaced by a furan ring in ranitidine and a thiazole ring in famotidine.

Figure 2 Compounds leading to the synthesis of omeprazole, the first PPI.

Pyridinyl-2-ethylamide

Pyridinyl-2-ethylthioamide

2-Pyridylmethythio-benzimidazole

Timoprazole (1975)

Figure 2 Compounds leading to the synthesis of omeprazole, the first PPI.

Was this article helpful?

0 0

Post a comment