INTRODUCTION:

A peptic ulcer is a chronic disease in which involve the complication of the gastrointestinal tract by identifying the mucosal damage secondary to gastric acid secretion and pepsin. It generally occurs the proximal duodenum and stomach and less occur in the distal duodenum, lower esophagus, jejunum, and ectopic gastric mucosa.

In united state peptic ulcer main cause by utilizing the helicobacter pylori infection and nonsteroidal anti-inflammatory drugs (NSAIDs) [1]. Helicobacter pylori infection has conducted the pepsin ulceration, gastric lymphoma, gastroduodenal inflammation and gastric cancer that have demonstrated by the report of human epidemiological and animal studies. In gastric epithelial cells H-pyloric persuades inflammatory associated gene expression and involving in nuclear factor kappa B (NF-κB) activation and increase the proclamation of cyclooxygenase-2 (COX-2), and fabrication of interlukevkin8 (IL-8), and inducible the syntheses of nitric oxide (iNOS) [2]. Most gastroprotective drugs react the offensive influence neutralizing acid secretion like H2 receptor blocker, antacids, ranitidine, pirenzepine, anticholinergic, proton pump inhibitor, lansoprazole, and omeprazole which involved in acid secretion but these antisecretory drugs may be related with ulcer relapse and adverse events [3]. Since from a long time, peptic ulcer disease was frequently lead with surgically, with the consequence of high mortality and morbidity rates. Elective 1980s decrease 85% peptic ulcer surgery, which allocated to the use of ranitidine, cimetidine, H2 RAs [4]. the evaluation of proton pump inhibitors (PPIs) and further upgraded the inhibition in the secretion of gastric acid and also deficiency of tachyphylaxis to proton pump inhibitor treatment which insures the gastric ulcer and duodenal healing rates is higher [5]. However the prevalence of peptic ulcer disorder in western countries has declined since 100 years, about 1 in 10 Americans are influenced [6]. Most recent studies of injury to gastric mucosa focused on increasing their resistance. Nitric oxide, lipoxin A4, PGs, mediators of mucosal defense [7]. In the past, some few years recognized that the improvement in our conception of mucosal defenses and gastric ulcer pathogenesis and the process of healing of ulcer [8].

Peptic ulcer classification:

Diagnostic technology and imaging has been improved and indicated different factors responsible for the pathogenesis of ulcer. In clinical practice currently seen the common ulceration causes which are summarized in table no.1

Table No.1: Summarizing multiple factors for ulcer [9].

	The factor responsible for ulcer
1	Drug-induced injury: NSAID, Aspirin, chemotherapy
2	Infection-induced inflammation: CMV, H-pyloric, HSV-1, Syphilis, TBC
3	Physical-mechanical trauma: balloon, Cameron, Nissen
4	vascular compromise: tobacco, vasculitis, ischemia
5	caustic injury: damage radiation
6	post-mucosal ablation
7	Inflammatory condition Idiopathic: Behcet’s Crohn’s
8	Aggravation through smoking
9	Acid hypersecreation+/- Idiopathic ulceration
10	stress: severe burn, CNS injury: Psychosocial

Pathogenesis of peptic ulcer:

Mechanism of gastric acid secretion:

The stomach is predominant for digestion food. Acid and enzyme are releases in the stomach by the existence of stimulating food. The mechanosensitive and chemoreceptor occur in stomach are activated by the existence of food to produces certain responses. Binding of G-protein coupled receptors by gastrin, histamine, and Ach that activate the system of second messenger [10]. Acid is secreted parietal cell in the gastric gland. The acid secretion physiological regulation by parietal cells which is important in factor to abbreviate in gastric acidity. The three vital pathways for animate the secretion of parietal acid such are 1) vagus nerve stimulates the neuronal system. 2) release of histamine locally stimulated by paracrine through enterochromaffin-like cells. 3) gastrin release through from antral G cells stimulated by endocrine. In the pathway of the neuronal system, vegal nerve releasing acetylcholine and gastric acid secretion is stimulated by muscarinic M3 receptor through parietal cells on the basolateral membrane. The CNS is deliberation the main feature for originating secretion of gastric acid by reaction of food anticipation. From gastric antrum Gcells through gastrin and fundus having enterochromaffin-like that possess histamine and their release stimulation by involving of indirectly acetylcholine. The parietal cells having acid secretion which consist of the gastric histamine and their main sources were ECL cells. The binding to H2 receptor in paracrine fashion in parietal cells was activates by the release of histamine from HCL. In antral G cells primarily occur gastrin. The activation of central neural, chemical composition and local distension of gastric content having a gastrin release by their regulation [11]. The influence of gastrin and vegal stimulation the histamine release from a mast cell and paracrine-ECL cells. Expend the level of intracellular Ca2+ through cyclic AMP, Ach/gastrin via histamine that causes acid secretion [12]. H+/K+ ATPase stimulates the last step in acid secretion. which is also termed as a gastric proton pump. cAMP or Ca2+ ion-dependent pathways activation or H+/K+ ATPase activation from parietal cells [13] Fig.1

Figure.1: Showing the gastric acid secretion mechanism [14].

Pathophysiology of peptic ulcer:

The recent Advances showing the improvement of understanding the pathophysiology of peptic ulcer. ulcer disease are a disproportion between pepsin and acid and mucosa digestion inactivity of digestive. The three viable etiology group of peptic ulcer. 1) In Zollinger-Ellison Syndrome was occur the enormous hypersecretion of acid peptic. 2) by occurring nonsteroidal anti-inflammatory drugs (NSAIDs). 3) By the helicobacter pylori infections associate the ulcer. in the patient of duodenal ulcer, the abnormalities in the number of acid secretion were founded, which universal facts. The mass of parietal cell 1.5 to 2 times frequency increases [15].

Pepsin:

Pepsinogen1 (PG1) is the originated of ulcer disease [16]. That has been discovering superficial gastritis which originated by H. Pyloric [17]. In children, the treatment of H. Pyloric resulted in the depilation in PG1 level serum. But that depilation in PG1 serum level results in the activity of lower luminal pepsin was unknown. In some patient of the duodenal ulcer; seen the liquid consisting gastric emptying, gastric acid overcomes capabilities of neutralization duodenal acid were allowed and determine the abnormalities [18].

Acid:

Acid secretion in a normal condition was depending on neural (vegal), gastrin (endocrine), and Histamine (paracrine limbs). Pepsin and acid secretion frequency increase after ingestion of meal because of cephalic activation via vegal nerve as well as gastric secretion of the parietal cell. Lowering on pH of duodenal and gastric return to baseline of acid secretion and inhibition of gastric release [19].

Mucosal protection:

The gastrointestinal mucosa was protected by the powerful effects of digestive of pepsin and acid is a vitally important in biologic [20]. When luminal pH is low 1.5, maintain the above pH 6 of duodenal mucosa and gastric. The epithelial cell affects peptic destruction and resists acid. The connection between gastric epithelial cells with tight junctions was assisted to prevent penetration of acid. The surface of an apical cell of gastric mucosa the monolayer was complying with acid flux and transmembrane electrical potential maintained by in vivo consist variability for 4 hours at pH 2 [21]. Occurring mucosal breaks then moves epithelial through with basement membrane [22].

Abnormal Mucus:

In gastric ulcer patient, duodenal ulcer having duodenal mucosa and gastric protected by mucus layer. Patient of ulcer disease has increased in the segment of dextrans in low molecular weight, which occurs weaker mucus [23]. Gastric mucus having physical properties is altering between controls and ulcer patients. By goniometry, the hydrophobicity was assessed on gastric mucus. In gastric ulcer patient and duodenal and control in dyspeptic. The hydrophobicity having a significant reduction in groups of patients of ulcer disease. H. Pyloric gastritis occurs a compelling decreasing in controls of hydrophobicity [24]. The production of prostaglandin is important in deplication of mucus. Endogenous occurs prostaglandins and mediators production in mucus [25].

Blood flow:

In any tissue blood flow is very important to maintain the integrity of gastroduodenal. Difficult to say that the reduction in mucosal blood flow is clinically vital use in ulcer disease. In acute lesion formation, the results of decreasing in blood flow were gastroduodenal mucosa having large data showing on the animal. Duodenum is more resistant to the ischemia in rats stomach. Till the flow is decreasing below a conception of baseline 40% the gastric lesion is not determined. Formation of the duodenal lesion has linearly decreased flow in the absence of threshold level, development in the hemorrhagic mucosal lesion. Without increasing baseline flow prevent the vascular changes by pretreatment with sodium thiosulfate or dimethyl PGE2 [26].

Modern treatment of ulcer disease:

Antacids:

An antacid is the first agents for the treatment of ulcer disease [27]. The outcome of postprandial acid after ingestion of antacid was to increase the gastric juice level by an average of 16% [28]. The side effects were increased in gastric secretion, gastrin release, duodenal acid level, and gastric emptying. The average of the patient is 25% they suffered from duodenogestric reflux and diarrhea [29]. Gastrin, H2 receptor, carbamyl-choline, acetylcholine receptor are showing the interaction and appear as a form sensitize cell as gastrin cells. Antacid treatment aims to increase in pH 3.0 in the endpoint of gastric content and reduces the activity of pepsin for conversion between Pepsinogen into pepsin. In GU duodenum which was having properties bile-acid binding play a pathogenic role by increasing the gastric reflux. The four major antacid types: aluminum hydroxide, carbonate, calcium, magnesium. All these types were important for consisting the combination of acid to antacid. Changing in the movement of the bowel is combined constipation was constantly [30].

Pyroloplasty and SPV:

At Munich surgical clinic 1407 ulcer of duodenal and 308 ulcers of gastric were diagnosed between 1964 and 1982, with selective proximal vagotomy (SPV) and non-resulting method and Pyroloplasty of function and form either open or submucous and as required excision of the ulcer [31]. 11 days, 45, days, annually the combination of the examination with biopsy and endoscopy from the antrum and fundus and preoperatively and postoperatively their result were achieved in 5-7 years over a period. Reduction in basal acid output 90% clinically showed in 89% of the patient, reduction in diameter of 21% in mucosal postoperative having 75% maximal acid output and despite a continuous chief cell are increased. In 90% cases amelioration pain, 75% increasing weight, 1.8% in dumping, consisting 2% diarrhea, 2.7% recurrence in DU, GU contain 7.3%, 0.5% mortality [32]. Up to 16% in GU and 10% in DU were increased in the stomach antrum occurs the Pyroloplasty and SPV. 7% consist of preoperative maximum GC, few years the surgery in the stomach was continuously increased. In GU or DU having not occurring an inflammation preoperatively but seen in fundus ventriculi. Instead of morphological variation after a sole treatment SPV plus Pyroloplasty, the amount of acid secretion has been diminished for years. The recurrence probability of DU and GU low down at 24% for 4 years. It is not important to have pharmacological interaction. the SPV complication rate is zero [33].

Pirenzepin:

Pirenzepin is a drug class of anticholinergic. Acetylcholine mediated the stimulating acid and pepsin secretion in vagus nerve [34,35]. The structure of tricycle compound similar to pirenzepine, in absences of central nervous system activity, consisting of a peptic ulcer disease originating against the drug. Anticholinergic drugs are not affected by the gastric mucosal barrier and hydrogen ions with mucosal permeability like atropine. The dose of pirenzepine inhibits the pentagastrin and basal, by decreasing the volume of pH of secretion occurs gastric stimulated by gastrin. Nocturnal acid output and basal are 30 to 40% reduces and 30 to 40% maximal acid output [36].

Histamine H2 receptors:

In body histamine stored and produced in a chemical form. It is a messenger molecule and occurs to regulates physiological function [37]. Its release from electrochromaffin-like cells, mast cell, neurons. The action of histamine is arbitrated by histamine receptors (H1, H2, H3, and H4). Histamine belongs a class of A GPCRS and subfamily of amine. In stomach acid secretion are stimulated by histamine which causes peptic ulcer and also consisting an integral membrane protein [38]. In clinical practices H2-receptor antagonist introduced in 1976, peptic ulcer disease in a patient with acute management is a few problems. Administration of ranitidine and cimetidine for four-week ulcer healing inpatient more than 90% with duodenal ulcer [39,40].

For prophylaxis, the three main areas were H2-receptor antagonist are used on intensive care unit duodenal ulcer or prevention of gastric drug-induced, prevention off stress-induced ulceration, and after haematemesis protection from rebleeding. The incidence of perforated ulcer or NSAID-induced bleeding was reduced by studies of prophylaxis with H2-receptor antagonist [41]. The administrations of H2-RA in dogs are described in pharmacokinetic studies [42]. Ranitidine, cimetidine, and famotidine gave on empty stomach they well absorbed orally 70-75% with a bioavailability. Peak plasma concentration of ranitidine and cimetidine was increased within 30 min and for famotidine within 2 hours. When cimetidine given with food the peak plasma concentration may be decreased or delayed. The half-life of cimetidine is very short (1.6). Ranitidine and famotidine half-life was long [43,44]. In human, elimination of ranitidine and cimetidine and famotidine involve a combination of tubular excretion, hepatic metabolism, and glomerular filtration [45,46]. 50% elimination of oral cimetidine by hepatic metabolism by conjugation and hydroxylation and elimination by renal excretion is 50% [47]. Of cytochrome P450 function cimetidine is a potent inhibitor, which effects on drug interaction and hepatic metabolism of other drugs. With a combination of tubular secretion and glomerular filtration, ranitidine shows 70% elimination through a urinary excretion [48].

Proton pump inhibitors:

In gastric acid secretion through parietal cells proton pump inhibitors is ultimate mediators [49]. The omeprazole was initial drugs are available which inhibited the H+/K+ ATPase pump through a parietal cell. Some related compounds are rabeprazole, lansoprazole, esomeprazole, pantoprazole [50,51]. Other proton pump inhibitors and omeprazole are weak bases and also occurs pro-drugs because inactive form they metabolized [52,53]. Mostly all proton pump inhibitors are weak bases and administrated by oral formulation to protect from degradation by stomach acid they pass through the small intestine. There are three approaches are used to control the instability of proton pump inhibitors in an acid condition of a stomach. The first approach is the enteric-coat drugs soluble in alkaline and neural in the small intestine and insoluble in the stomach. In current time include containing capsule with multiple enteric-coated pellets, enteric-coated tablet and orally disintegrating tablet which contain with enteric-coated micro granules. These all in form of delayed-released. In each granule, some capsule contains a few numbers of enteric-coated micro granules [54]. The second approaches are during absorption phase proton pump inhibitors protect from an acidic condition with mix with sufficient amount like sodium bicarbonate that contains pH of the stomach through neutral or alkaline pH. This phase is immediate-release because of proton pump inhibitors are not enteric-coated [55,56]. In the last approach, the formulation of PPI is absorbed and dissolves fastly and decreases in time when drugs contact with stomach acid. All approaches are described in table no.2 [57].

Table No.2: Proton Pump inhibitor Formulation Available for Administration in Small Animal [58]

S.NO	Brand name (molecules)	Available dose	Administration	Formulation	Release
01	Prevacid (lansoprazole)	15 to 30mg	Oral route administration	Capsule Formulation	Retard release
01	Prevacid (lansoprazole)	15 to 30mg		Orally decaying tablet	Retard release
02	Protonix (Pantoprazole)	20mg to 40mg	Oral route administration	Tablet Formulations	Retard release
		Weighing up to 40mg	Oral route administration	Powder for Intravenous use stable 28 days or mix 4mg/ml in polypropylene syringe at temperature 2 to 8^oC or 3 days in glass vial temperature 22 to 28^oC	Rapid release
		40mg per vial	Intravenous (IV) route		Retard release
03	Nexium (Esomeprazole)	20 to 40mg	Oral Route administration	Capsule formulation Powder	Rapid release
03	Nexium (Esomeprazole)	40mg per vial	Intravenous (IV)Rout	preparations are stable 2 days at 23^oC and 5 days 4^oC or mix 0.8mg/ml in polyvinyl chloride bags.
04	Gastrogard (Omeprazole)	Graduated Weight Upto 4mg/kg	Orally administration	Paste formulation Suspended by diluted in sesame oil 1.9)	Rapid release
05	Prilosec (Omeprazole)	10mg to 40mg	Capsule dispense by opening of micro granules	Capsule accompanied by enteric-coated micro granules	Retard release

H. Pylori infection:

Currently, H-pylori infection is an important ulcerogenic factor in the stomach. The interaction between gastric acid secretion and H. pylori infection occurs several implications. In high concentration of gastric juice, hydrochloric acid has an effect of strong bactericidal as well as H. pylori [59]. However, H. Pylori persist in colonize and stomach the gastric mucosa of a patient with disease gastritis and peptic ulcer [60]. The relation between in gastric acid secretion and H.Pyloric is the low prevalence of antral colonization inpatient of pernicious with the bacterium. In a potential study, antral biopsies consider 11% form such patient and H.Pylori consider 71% in controls [61]. In duodenal ulcer patient, the serum gastric level which is meal stimulated is higher in comparisons to non-ulcer controls. Patients who have symptoms of positive H-pylori have higher meal stimulated the level of serum gastrin levels. These levels trends to slow down when there is cardication of H. Pylori [62,63]. Only H. Pylori elimination is an efficacious treatment for both gastric ulcer and duodenal [64].

CONCLUSION:

A peptic ulcer is a disease in which involve the complication of the gastrointestinal tract by identifying the mucosal damage secondary to gastric acid secretion and pepsin. The pathogenesis of peptic ulcer the binding to H2 receptor in paracrine fashion in parietal cells was activates by the release of histamine from HCL. In antral G cells primarily occur gastrin. The activation of central neural, chemical composition and local distension of gastric content having a gastrin release by their regulation. In treatment of peptic ulcer is Antacids, Pyroloplasty and SPV, Histamine H2 receptors, Pirenzepin, Proton pump inhibitors, H. Pylori infection have been recently used.

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Received on 16.09.2019 Modified on 30.09.2019

Res. J. Pharmacology & Pharmacodynamics.2019; 11(4):165-170.

DOI: 10.5958/2321-5836.2019.00029.6