Gastric Secretion Peptic Ulcer and Anticholinergics as Antiulcer Agents

The pathophysiologyof peptic ulcer is not fully known and, in the present state of knowledge, it is not possible to present the pertinent normal physiology briefly. For a detailed discussion on the physiology and chemistry of gastric secretion and the pathologic physiology of peptic ulcer, reference should be made to reviews on the subject (1-5). The following is a brief summary of the gastric secretion and its relationship to peptic ulcer, a knowledge of which is necessary to understand the problems of developing antiulcer agents.

Gastric juice contains a mixture of water, inorganic ions, hydrochloric acid, pepsinogens, mucus, various polypeptides, and the intrinsic factor. Pepsinogens are precursors of the proteolytic enzymes, pepsins. They are readily converted into the corresponding pepsins by either acid or pepsin itself. Conversion by acid is instantaneous at pH 2.0. In humans, gastric juice contains hydrocholoric acid during the period of interdigestive secretion as well as during the period of digestive secretion. Although the mechanisms of interdigestive secretion are not known, they depend partly on the tonic activity of the vagus. The gastric secretory activity during the period of digestive secretion may be divided into three phases, cephalic, gastric, and intestinal. Each phase is named to denote the region in which the stimuli act to induce gastric secretion.

In the cephalic phase the stimuli are initiated in the central nervous system. The stimuli are the sight, smell, taste, and thought of food, which act through conditioned and unconditioned reflexes. The final efferent path is the vagus nerve. The impulses in the vagus nerve stimulate the secretory cells in the gastric glands. Acetylcholine, which is released from the postganglionic nerve endings, exerts a direct action on the secretory cells. Administration of atropine abolishes this phase. The secretion is high in acid and pepsinogens, and its concentration of mucus is lower than that of the basal secretion; mucus output rises 8-10 times as the volume increases.

The gastric phase of secretion begins copiously as soon as the food enters the stomach, and it may continue 3-4 h, with a total volume of 600 mL or more of strongly acid juice contain ng a high concentration of pepsinogens. The gastric phase of secretion is caused by local and vagal responses to distension and by the hormone gastrin, released by the musosa of the pyloric gland area. The local nerves of the pyloric area are confined to the mucosa and are cholinergic. Irrigation of the pyloric gland area with acetylcholine releases gastrin, and this liberation of gastrin is abolished by atropinization. There is a synergism between gastrin and acetylcholine at the target cells; the effect of injected gastrin on both acid and pepsinogen secretion is increased two- to eightfold by subthreshold parasympathomec-tic stimuli, and it is strongly inhibited by atro-pinization.

The intestinal phase that begins when chyme passes from the stomach to intestine, contributes about 10% of the total response to a test meal. Protein and its digestion products, milk, dilute alcohol, and acid itself are effective stimulants. Although there may be a ner vous component, the intestinal phase includes humoral stimulation of secretion by unknown agents. Gastrin released from the small intestine may be involved. The response to whatever humoral agent comes from the intestine is greatly increased when subthreshold doses of cholinergic drugs are given.

A number of humoral inhibitors of gastric secretion arise in the small intestine. They are termed enterogastrones. An enterogastrone is present in the jejunum and duodenal mucosa. It is released in the presence of fat and inhibits gastric secretion and motility. The hormone secretin, which stimulates pancreatic secretion, is an enterogastrone. It is produced in the proximal duodenum and inhibits gastric secretion in the presence of acids. Cholecystoki-nin, which is the same as pancreozymin, and gastrin share the same terminal tetrapeptide. Given alone, cholecystokinin is only a mild stimulant of gastric acid secretion. It is a competitive inhibitor of the receptor for gastrin, which is a powerful stimulant of gastric acid secretion. Therefore, in the presence of gas-trin, cholecystokinin decreases the total output of acid. Glucagon (and possibly enteroglu-cagon) reduces the gastrin-induced acid secretion by noncompetitive inhibition of the receptors to gastrin. A gastric inhibitory polypeptide (GIP) that is present in duodenal mucosa inhibits both histamine- and gastrin-induced acid secretion. A vasoactive intestinal peptide (VIP), which has been isolated from small intestinal mucosa, inhibits histamine-induced acid secretion. GIP and VIP are two possible enterogastrones whose significance has yet to be established.

Histamine, the exact role of which is not clearly understood, stimulates secretion of gastric juice that is rich in hydrochloric acid. Recently, histamine receptors have been divided into three types, HI, H2, and H3. Stimulation of H2 receptors by histamine results in increased gastric acid secretion. H2 receptor antagonists (burinamide, metiamide, cimeti-dine) inhibit histamine-induced gastric acid secretion in both humans and animals. In humans, H2 antagonists inhibit not only his-tamine- but also pentagastrin (a synthetic analog of gastrin)-stimulated gastric acid secretion. This suggests that, at least in humans, gastrin acts partially by histamine. Blockage of acetylcholine receptors by atropine and his-

Anticholinergics (ACh)

-Vagus nerve

H2-receptor antagonists (H)

Histamine

Antrum

Anticholinergics (ACh)

-Vagus nerve

H2-receptor antagonists (H)

Histamine

Antrum

^ Small . intestine

Histamine Gastric Ulcer

Local, hormones: TTX prostaglandins (G, H)

PGE^ PGA1

Mucus sécrétants (carbenoxolone)

Enterogastrones Secretin (G)

Figure 3.1. Interactions among neuronal and hormonal factors and pharmacological agents during cephalic (Cp), gastric (Gp), and intestinal (Ip) phases of gastric acid secretion by parietal cell. ACh, acetylcholine; GIP, gastric inhibitory peptide; VIP, vasoactive intestinal peptide; MI, muscarinic receptor; H2, histamine H2 receptor; GR, gastrin receptor; (+), stimulation of acid secretion; (-), inhibition of acid secretion. In parentheses, next to the inhibitory agents, is indicated the blocked stimulant agent (ACh, acetylcholine; H, histamine; G, gastrin).

^ Small . intestine

Enterogastrones Secretin (G)

Local, hormones: TTX prostaglandins (G, H)

PGE^ PGA1

Mucus sécrétants (carbenoxolone)

Enteroglucagon (G) Cholicystokinin (G)

, 1f,Pepsin inhibitors (sulratea polysaccharides)

Figure 3.1. Interactions among neuronal and hormonal factors and pharmacological agents during cephalic (Cp), gastric (Gp), and intestinal (Ip) phases of gastric acid secretion by parietal cell. ACh, acetylcholine; GIP, gastric inhibitory peptide; VIP, vasoactive intestinal peptide; MI, muscarinic receptor; H2, histamine H2 receptor; GR, gastrin receptor; (+), stimulation of acid secretion; (-), inhibition of acid secretion. In parentheses, next to the inhibitory agents, is indicated the blocked stimulant agent (ACh, acetylcholine; H, histamine; G, gastrin).

tamine receptors by H2 antagonists results in reduction of the effectiveness of gastrin to induce acid secretion.

Therefore, there seems to be a complex interaction among the three receptors, acetyl-choline receptors, H2 receptors, and gastrin receptors involved in the acid secretion by parietal cells.

Among local hormones and messengers, prostaglandins (PGE,, PGA^ adenosine 3',5'-monophosphate (cyclic AMP, cAMP) inhibit both pentagastrin- and histamine-stimulated gastric secretion. According to present evidence, all hormones that reduce gastric acid secretion increase both adenylcyclase and in-tracellular cAMP activity. Conversely, all hormones that primarily stimulate gastric acid secretion reduce intracellular cAMP levels. Therefore, cAMP is involved in the final links of gastric acid secretion.

The interplay among various neuronal and hormonal factors in the gastric acid secretion by the parietal cell during cephalic, gastric, and intestinal phases are schematically shown in Fig. 3.1. In addition to being inhibited by atropine-like agents and enterogastrones shown in Fig. 3.1, the acid secretion is inhibited by gastrone in the mucus of human stomach, by urogastrone isolated from the urine of men and dogs, by strongly acid solutions in the duodenum, and by stimulation of the sympathetic nervous system.

Peptic ulcer occurs in the pyloric region of the stomach or the first few centimeters of the intestine. The gastroduodenal muscosa is exposed constantly to mechanical, physical, and chemical insults, some of which have already been described. A peptic ulcer does not develop without the presence of a pepsin-containing juice of such low pH that it can exert a peptic influence on the gastric wall itself. The extent of this insult is determined by the number of acid- and pepsinogen-producingcells, their irritability, and/or the magnitude of the stimuli that reach them. These stimuli are partly nervous (vagal) and partly hormonal (gastrin, corticosteroids).

The healthy stomach does not digest itself. Counteracting the aggression are defensive factors such as buffering and dilution by food, inhibition of the secretion of gastric juice, and drainage of gastric contents. In addition, however, the local condition of the mucosa (the mucosal resistance) is also of importance. Some of the determinants of mucosal resistance are the mucous barrier, the local circulation, and the healing capacity of the mucosa. A peptic ulcer forms when the insult is more powerful than the defense. In the case of duodenal ulcers, the powerful irritation is often the important factor; in gastric ulcers it is the insufficient defense.

The ideal agent for the treatment of the peptic ulcer would be one that selectively inactivates pepsin or inhibits the output of hydrochloric acid so as to maintain the pH of the gastric contents at about 4.5 for long periods after its oral ingestion. It should produce no, or only minimal, side effects, induce no tolerance, and be inexpensive. It should be effective during all periods and phases of gastric secretion and prevent the formation of ulcers.

Atropine-like anticholinergics do not satisfy all requirements of an antiulcer agent. They block acetylcholine action at the neu-roeffector junction of the vagus. They give relief to patients with a peptic ulcer by their antisecretory and antispasmodic effects. They decrease the basal hydrochloric acid and pepsin secretion, thereby allowing the healing of ulcers. The antispasmodic effects of atropine-like agents are as consistent as their antisecretory effects. Motor activity is closely related to ulcer pain, and the pain-relieving action of an-ticholinergic agents seems to be related to their effect on depressing motor activity (antispasmodic effect).

An "effective" atropine-like anticholinergic drug is capable of favorably influencing the excessive gastric secretion under certain conditions. It exerts a significant effect on acid secretion during the basal and interdigestive night secretion to the point of abolishing it completely for many hours (6). Its effect on secretion during the feedingof milk and cream is significant (7, 8). However, anticholinergic drugs do not effectively perform a "medical vagotomy" and they do not effectively reduce gastric acidity to the extent of achlorhydria when patients are fed (8,9). The effective anticholinergic agent as an antiulcer drug should be selective for the subtype of muscarinic receptors localized on the secretory cells of gastric glands as well as mucosa of the pyloric gland area. Anticholinergics selective for muscarinic receptors of Ml subtype are useful in decreasing gastric acid secretion.

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Responses

  • Rebecca
    Why are anti cholinergics not effectively used as antiulcer agent?
    3 years ago
  • Quintilio
    Why anticholinergics are not effective as antiulcer agents?
    3 years ago
  • michaela davidson
    How does anticholinergic drugs treat ulcer drugs?
    2 years ago

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