**2. The conventional therapy for stomach ulcer management**

SU therapy has witnessed many strides over the last decades and a number of drugs are now available for its treatment. Since the occurrence of SU disease is attributable to either pepsin action and hyperacidity or inadequate mucosal resistance, hence, its effective management lies exclusively in stemming the aggressive factors or fortify the defensive mechanisms. A corner stone in this approach was the advent of histamine H<sup>2</sup> -receptors and the respective antagonist [15], which signified a landmark achievement in the management of disorders characterized by gastric hypersecretion. The H<sup>2</sup> -antagonists were instantaneously identified as potent and safe agents which may replace the previously used drugs. For instance, the appearance of cimetidine (an H<sup>2</sup> -antagonist agent), led to the virtual disappearance of drugs of unknown mechanism like gefarnate, sulphoglycopeptide, amilopectine, zolimidine, xylamide, etc. Despite the inherent improvement witnessed with the use of the H<sup>2</sup> -antagonist over the previously used drugs, their untoward reactions have undermined their appreciable application. Generally, the antiulcer drugs may be classified according to the site and/ or mechanism of action as: (a) antacids; (b) gastric muscle stimulants; (c) agents which protect the mucosa, increase mucosal resistance or coat ulcer craters; (d) antisecretory drugs, which may be anticholinergic agents; (e) corticohypothalamic drugs; and (f) proton pump inhibitors.

#### **2.1. Antacids**

It is noteworthy that either antacid mixtures or combinations of antacids with other compounds are more commonly used than single-entity antacids [15]. These kinds of formulation have been made to elicit a better neutralizing effect and to extenuate side effects associated with single constituent entities. The calcium and aluminium combinations reduce diarrhea while magnesium caters well for constipation. Similarly, a combination of slow- and fastacting agents could increase the total buffering time. More improved benefits are claimed for mixtures having alginic acid (a foam-forming agent), which floats above the gastric juice with eventual aiding of contact between the antacid and the mucosa. In the event of gastroesophageal reflux, the alginic acid appears to prevent reflux by being the first to come in contact with the esophagus. By so doing, further erosion by the gastric acid is effectively prevented. Also, when simethicone (dimethylpolysiloxanes with characteristics antifoaming and water-repellant properties) is used, defoaming the gastric juice to reduce flatulence and gastroesophageal reflux is achieved. However, the resulting contributory adverse effects of the respective constituent in the antacid especially gastric irritation are a major challenge consistent with the use of antacids.

#### **2.2. Gastric muscle stimulants**

In individuals with stomach atony where there is consequential prolonged contact time between acid and mucosa due to the delay in gastric emptying, stimulants of gastric motility produce satisfactory outcomes. Domperidone and metoclopramide are the two most widely used compounds in this category. While both accelerates gastric emptying in experimental animals and humans, the metoclopramide still acts via other four important mechanisms that have made it more potent: (i) a cholinergic effect on muscarinic receptors; (ii) a direct effect on smooth muscle; (iii) an effect on specific centers regulating gastrointestinal motility; and (iv) a release of motilin which could be strongly responsible for the effects on the proximal bowel [15].

#### **2.3. Mucosa protecting agents**

corner stone in this approach was the advent of histamine H<sup>2</sup>

characterized by gastric hypersecretion. The H<sup>2</sup>

appearance of cimetidine (an H<sup>2</sup>

consistent with the use of antacids.

**2.2. Gastric muscle stimulants**

inhibitors.

26 Stomach Disorders

**2.1. Antacids**

antagonist [15], which signified a landmark achievement in the management of disorders

as potent and safe agents which may replace the previously used drugs. For instance, the

of unknown mechanism like gefarnate, sulphoglycopeptide, amilopectine, zolimidine, xyl-

over the previously used drugs, their untoward reactions have undermined their appreciable application. Generally, the antiulcer drugs may be classified according to the site and/ or mechanism of action as: (a) antacids; (b) gastric muscle stimulants; (c) agents which protect the mucosa, increase mucosal resistance or coat ulcer craters; (d) antisecretory drugs, which may be anticholinergic agents; (e) corticohypothalamic drugs; and (f) proton pump

It is noteworthy that either antacid mixtures or combinations of antacids with other compounds are more commonly used than single-entity antacids [15]. These kinds of formulation have been made to elicit a better neutralizing effect and to extenuate side effects associated with single constituent entities. The calcium and aluminium combinations reduce diarrhea while magnesium caters well for constipation. Similarly, a combination of slow- and fastacting agents could increase the total buffering time. More improved benefits are claimed for mixtures having alginic acid (a foam-forming agent), which floats above the gastric juice with eventual aiding of contact between the antacid and the mucosa. In the event of gastroesophageal reflux, the alginic acid appears to prevent reflux by being the first to come in contact with the esophagus. By so doing, further erosion by the gastric acid is effectively prevented. Also, when simethicone (dimethylpolysiloxanes with characteristics antifoaming and water-repellant properties) is used, defoaming the gastric juice to reduce flatulence and gastroesophageal reflux is achieved. However, the resulting contributory adverse effects of the respective constituent in the antacid especially gastric irritation are a major challenge

In individuals with stomach atony where there is consequential prolonged contact time between acid and mucosa due to the delay in gastric emptying, stimulants of gastric motility produce satisfactory outcomes. Domperidone and metoclopramide are the two most widely used compounds in this category. While both accelerates gastric emptying in experimental animals and humans, the metoclopramide still acts via other four important mechanisms that have made it more potent: (i) a cholinergic effect on muscarinic receptors; (ii) a direct effect on smooth muscle; (iii) an effect on specific centers regulating gastrointestinal motility; and (iv) a release of

motilin which could be strongly responsible for the effects on the proximal bowel [15].

amide, etc. Despite the inherent improvement witnessed with the use of the H<sup>2</sup>





Compounds like sucralfate, carbenoxolone and chelated bismuthate belong to this class of drugs. The sucralfate (a complex of sucrose and aluminium hydroxide) potentiates its action by inhibiting gastric hydrolysis with significant affinity for ulcerated mucosa. It forms a complex with susceptible proteins (fibrinogen, albumin etc) that adhere to the ulcerated area, thereby shielding against acid, pepsin action and penetration of bile acid. The merits of sucralfate over other antiulcer drugs relate to a lack of systemic effect due to the poor absorption of the compound [16]. The disadvantages include a certain delay in gastric emptying and constipation which affects almost 2% of the sufferers. Furthermore, compliance is another issue of concern as sucralfate must be taken four times daily (q.i.d.) and at least one hour before meals to be optimally effective. While chelated bismuthate and carbenoxolone works quite similar to sucralfate, appreciable incidence of aldosterone-like adverse effects (sodium and fluid retention, hypertension etc) have hampered their use.

#### **2.4. Drugs with antisecretory effect**

#### *2.4.1. Anticholinergics*

Despite that the drugs in this class have been used for many years, information on their ulcer healing capacity is still elusive. This may be attributable to the radiological method that was initially used but later found not to be very effective in wound healing assessment. Hyoscyamine, atropine, phentonium, propantheline and methantheline with characteristic ganglion-blocking and antimuscarinic effects are the classical examples of anticholinergics. Subsequent to the discovery and acceptance of the H<sup>2</sup> -antagonists, the anticholinergics virtually disappeared due to inherent adverse effects of dry mouth, blurring of vision, delay in gastric emptying, tachycardia, possible constipation, and urinary retention.

#### *2.4.2. H2 -antagonists*

Undoubtedly, the H<sup>2</sup> -antagonists are the most significant agents for the management and treatment of SU and for pathological conditions characterized by hyperacidity. Burimamide (the prototype of H<sup>2</sup> -antagonists) was faced-out because of low oral activity and toxicological concerns. Similarly, metiamide (the 2nd agent in the series), was orally active but potentiated significant bone marrow toxicity in clinical trials. Cimetidine (still the most widely used antiulcer drug), is the 3rd drug in this class and well over 70 million sufferers have so far benefitted from its pharmacological efficacy till date. This was closely followed by ranitidine, which was the first agent with an alkyl furan ring, which substituted the imidazole ring of the preceding H<sup>2</sup> - antagonists. More recent reports however suggest that optimum H<sup>2</sup> antagonism may also be achieved also with other different agents. For this class of drugs, not only could potency and efficacy be optimized, the pharmacokinetics could also be modified with the known duration of action of 4–6 h, exclusive to the 'short-acting' H<sup>2</sup> -blockers [17], optimized to and beyond 24–48 h to have 'long-acting' H<sup>2</sup> -blockers. Generally, over the last three decades, the most frequently used H<sup>2</sup> -antagonists in clinical practice are cimetidine, ranitidine and famotidine [2]. However, many adverse reactions such as effects on the endocrine, cardiovascular and central nervous systems (CNS) have been associated with these drugs.

#### **2.5. Corticohypothalamic drugs**

A role has been established for the CNS in the regulation of gastric secretion and in the pathogenesis of peptic ulcer, although clarification is required in many areas. It is not surprising that drugs which act specifically on the CNS may exert a beneficial effect on SU, which sometimes is significantly better than other drugs. Trimipramine is a tricyclic antidepressant which causes a slight decrease in gastric secretion that is apparently not connected with its anticholinergic action. Like other traditional tricyclic antidepressants, it may have some H<sup>2</sup> antagonistic effects and may also act on α-adrenoceptors enhancing catecholamine availability at central synapses [18], or may depress central vagal function. However the use of trimipramine in non-depressed ulcer patients is questionable.

#### **2.6. Proton pump inhibitors (PPIs)**

At present, PPIs are the most commonly prescribed class of antiulcer drugs. Their mode of action involves blockage of the site of gastric acid secretion in the parietal cell of the stomach [19]. However, because the parietal cells are constantly reproducing in millions, effective inhibition of gastric acid secretion is almost unachievable and this partly explains their relative safety compared to other groups of antiulcer drugs. In general, the incidence of short-term adverse effects subsequent to PPI usage is relatively low and this may be the reason for their being well tolerated. Their long-term use has not been frequently studied and the dearth of information in this regards has made it difficult to make definitive statements [20]. For all the PPIs (omeprazole, lansoprazole, dexlanprazole, esomeprazole, pantoprazole, rabeprazole and ilaprazole), the occurrence of adverse effects are similar, though they have been reported more frequently with omeprazole. This may be due to its longer availability. The common adverse effects with PPIs include headache, nausea, diarrhea, abdominal pain, fatigue and dizziness. Infrequent adverse effects may also include rash, itch, flatulence, constipation, anxiety, depression, myopathies and rhabdomyolysis [21].
