Prevention Of Gastroduodenal Ulceration Biology Essay

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Peptic ulcer represents a major health problem, both in terms of morbidity and mortality. Research advances during the last few years have offered new insight in the therapy and prevention of gastroduodenal ulceration by measures directed at strengthening the mucosal defense system rather than by attenuating the aggressive acid-pepsin factors held responsible for the induction of ulcers. The rise in gastric acidity and peptic activity are usually a manifestation of a physiological disturbance affecting one or more mechanisms which normally regulate gastric secretion. Neurotransmitters or hormones that directly stimulate secretion of hydrochloric acid and pepsin by the gastric glands are acetylcholine, gastrin and histamine. In addition there are other factors which play an important role in the manifestation of peptic ulcers. Activity of the gastric secretary cells has been found to be stimulated by caffeine, alcohol, hydroalcoholic acid, sodium chloride, non steroidal anti-inflammatory drugs (NSAIDs) and stress. There are two major components to the ulcerogenic effects of NSAIDs in the stomach, namely their topical irritant effects on the epithelium and their ability to suppress prostaglandin synthesis. The ability of NSAIDs to cause gastric damage correlates well with the ability to suppress gastric prostaglandin synthesis. There is also a time and dose dependency of both suppuration of gastric prostaglandin synthesis and ulcerogenic activity.

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Several components of gastric mucosal defense are influenced or mediated by prostaglandin, including mucus and bicarbonate secretion, blood flow, epithelial cell turnover and repair, and immunocyte function. Therefore, it is possible that inhibition of prostaglandin synthesis leads to a reduction in the ability of the gastric mucosa to defend itself against luminal irritants. Several other endogenous substances such as nitric oxide, polypeptides such as substance P and endothelin, autocoid comprising platelet activating factor, leukotrienes, serotonin, histamine and reactive oxygen species have also been found to play an important role in the gastroduodenal lesion.

The precise biochemical changes during ulcer generation are not clear yet, although various hypotheses have been proposed from time to time. Increased gastric motility (Garrick et al., 1986), vagal over activity (Cho et al., 1976), mast celldegranulation (Cho et al., 1979) decreased gastric mucosal blood flow (Hase and Moss, 1973; Kitagawa et al., 1979) and decreased prostaglandin level (Miller, 1987) during stress condition are thought to be involved in ulcer generation. Similarly role of oxygen derived free radicals have been shown to play a role in experimental gastric damage induced by ischemia and reperfusion (Perry et al., 1986), hemorrhagic shock (Itoh and Guth, 1985) and ethanol administration (Mizui and Doteuchi, 1986). Helicobarter pylori a pathogen is now known to be the most common and important causes of gastric ulcer in humans, exhibits active inflammation with epithelial damage accompanied by neutrophil migration.

For several decades, the adage, "no acid - no ulcer" has dominated the pharmacological basis of ulcer therapy, and the drugs used, reduced acid secretion. Not all patients, however, with gastric or duodenal ulcer have high acid secretion. In fact, only 30%-40% of cases with duodenal ulcer have hypersecretion of gastric acid and, in patients with gastric ulcer, acid secretion is either normal or low. In these cases, decreased mucosal resistance might be the dominant factor. Peptic ulceration results from an imbalance between acid-pepsin secretion and mucosal resistance. Since gastric acid is one of the major aggressive factor contributing to peptic ulcer disease, the reduction of gastric acid either by surgical or pharmacological intervention has been used to promote ulcer healing. Surgical treatment of peptic ulceration is usually either by vagotomy or removal of the diseased portion of the stomach.

More recently the role of mucosal factors in peptic ulceration has received considerable attention, and the term "cytoprotection" has been introduced to encompass the physiological processes which protect gastric mucosa from acid-pepsin digestion. Most of these cytoprotective mechanisms are related, at least in part, to endogenous prostaglandin secretion. The usual medical treatment for peptic ulcer is either by the inhibition of acid secretion or by neutralization of the acid. The neutralization of gastric acid can be done by antacid administration but their effectiveness is only for a brief period. Muscarinic antagonists such as atropine or pirenzipine are effective inhibitors of acid production. The histamine H2-receptor antagonist cimetidine, ranitidine and famotidine act as potent inhibitors (70-80%) of secretion. Complete inhibition of parietal cells acid secretion by receptor antagonist is difficult because of complexity of known receptors on parietal cells and a variety of second messenger signaling system coupled to these receptors which involve adenylate cyclase coupled with histamine receptor and intracellular Ca2+ with acetylcholine receptors. Thus, the most successful and desirable therapy is to inhibit the enzyme responsible for acid secretion. Gastric H+-K+ ATPase of the parietal cell is the H+ ion pump responsible for acid secretion in the stomach and has been identified as a pharmacological target for the development of drug to treat ulcers. Long lasting inhibition of the H+-K+ ATPase by drugs such as omeprazole, lansoprazole and timoprazole has been shown effective in the treatment of peptic ulcer disease. However, such agents irreversibly inactivate the ATPase and the return of acid secretion following such as inhibition requires denovo synthesis of new pump. This is the draw back of such type of inhibitors, because acid secretion is only achieved when new ion pumps are synthesized. This can be overcome by the use of reversible inhibitors of H+-K+ ATPase which may allow greater control over the duration of suppression of acid secretion. Other drugs, such as prostaglandins, carbenoxoline and sucralfate, stimulates mucus production. The negative charge conferred on mucous, particularly by its sulphate radicals, has resulted in to the development of new compound like the basic aluminum sucrose, octasulfate (sucralfate), which has properties similar to mucus. Thus, sucralfate and other cytoprotective drugs are effective in the management of peptic ulcer disease by their predominant actions on mucosal defensive factor.

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In addition, oxygen derived free radicals have been implicated in the pathogenesis o9f many diseases in many species. Oxygen radical are capable of damaging, reversibly or irreversibly the compounds of all biochemical classes, including nucleic acids, proteins, free amino acids, lipids, lipoproteins, carbohydrates and connective tissue macromolecules. These species may have an impact on such cell activities as membrane function, metabolism, and gene expression in the biological system; the oxidant of substrates is mainly affected by free radical such as reactive oxygen species (ROS) and reactive nitrogen species (RNS). Free radicals are species containing one or more unpaired electrons and are capable of independent existence. These are normal products of cellular aerobic metabolism. Superoxide (O2-) and hydroxyl (OH-) species are the predominant cellular free radicals. Hydrogen peroxide (H2O2) andperoxynitrite (ONOO-) although not themselves free radicals, contribute to the cellular redox state. Collectively these molecules are referred as reactive oxygen species (ROS). The major sources of ROS are mitochondrial oxidative metabolism, enzymatic reaction involving mixed-function oxidases and auto-oxidation of small molecules (Perry et al., 1986; Itoh and Guth., 1985).

Pharmacology of ulcer

What is ulcer

Ulcers are local defects on the surface of an organ produced by inflammation. Common sites for ulceration are the stomach, duodenum, intestinal ulcers, in typhoid fevers, instestinal tuberculosis, bacillary and amoebic dysentry, ulcer of legs due to varicose veins etc. peptic ulcers are very common.

Peptic ulcer arises from an imbalance between damaging factors within the lumen and protective mechanisms with in the stomach and duodenum. They occur most commanly (98-99%) in either the duodenum or the stomach in ratio of 4:1. Each of the two main types may be acute or chronic.

Acute peptic ulcer or stress ulcers are multiple, small mucosal erosions, seen most commony in the stomach but in occationally involving the duodenum. It is not clear how thw mucosal erosion occur in the stress ulcers because actual hypersecretion of gastric acid is demonstrable in only Cushing's ulcers occuring from intracranial conditions such as due to brain trauma, intracranial surgery and brain tumours.

Chronic peptic ulcers (gastric and duodenal ulcers), the two major of 'peptic ulcer disease' of the upper GI tract in which the acid-pepsin secretion is implicated in their pathogenesis. Peptic ulcers are common in the present-day life of the industrilize and civilized world.

Gastric and duodenal ulcers represent two distinct diseases as far as their etiology, pathogenesis and clinical features are concerned. However, pathological finding in both are similar and quite diagnostic.

Anatomy of an ulcer

The lining of the stomach and small intestine are protected by a self-lubricating mucous layer. Were it not for this layer of mucin, gastric acid (hydrochloric acid) would not only digest your food, but your stomach and intestine as well.

An ulcer can be thought of as a lesion or sore that along the stomach or intestinal wall where it can corrode muscle and blood vessels and cause bleeding, evidence blood in the stool. If this process is allowed to continue, bacteria and partially digested material can eventually leak into the abdominal cavity causing inflammation and severe pain. A perforated ulcer of this type usually requires immediate surgery. Ulcers can also occur in the duodenum and can restrict or block the intestinal opening, a condition that also demands immediate attention.

How do you know if you have an ulcer? Surprisingly, ulcers do not always produce symptoms. But, the most common symptom reported is burning pain between the breast bone and navel, usually occurring shortly after a meal or when the stomach is empty. An accurate diagnosis may involve an upper GI series or x-rays of the esophagus stomach and duodenum after drinking a barium cocktail. Other measures include blood and stomach tissue tests to determine if H. pylori are present (Karyn Siegel-Maier). Doctor say that in the United States, almost one in every 10 people will get an ulcer at some time during their lives.

Causes of ulcer

Acid-pepsin secretion

There is conclusive evidence that some level of acid-pepsin secretion is essential for the development of duodenal as well as gastric ulcer. Peptic ulcer never occurs in association with pernicious anaemia in which there are no acid and pepsin-secreting parietal and chief cells respectively.

Helicobacter pylori gastritis

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About 15-20% cases infected with H. pylori never develop duodenal ulcer in their life time while gastric colonization by H. pylori never develops ulceration and remain asymptomatic. However, there is evidence to suggest that increased density of H. pylori in the antrum is associated with greater likelihood of development of duodenal ulcer. H. pylori can be identified in mucosal samples by histologic examination, culture, increased activity, and serology (IgG and IgA antibodies to H. pylori).

Mucus secretions

Any condition that decreases the quality or quantity of normal protective mucus 'barrier' predisposes to the development of ulcer.

Gastritis

Some degree of gastritis is always present in the region of gastric ulcer, though it is not clear whether it is the cause or the effect of ulcer. Besides, the population distribution pattern of gastric ulcer is similar to that of chronic gastritis.

Local irritants

Pyloric antrum and lesser curvature of the stomach is the site most exposed for longer periods to local irritants and thus are the common sites for occurrence of gastric ulcers. Some of the local irritating substances implicated in the etiology of peptic ulcers are heavily spiced foods, alcohol, cigarette smoking, unbuffered aspirin, non-steroidal anti-inflammatory drugs etc.

Dietary factors

Nutritional deficiencies have been regarded as etiologic factor in peptic ulcer e.g. occurrence of gastric ulcer in poor socioeconomic strata, higher incidence of duodenal ulcer in the part of south india. However malnutrition does not appear to have any causative role in peptic ulceration in European countries and the U.S.

Psychological factors

Psychological stress, anxiety, fatigue and ulcer-type personality may exacerbate as well as predispose of peptic ulcer disease.

Genetic factors

People with blood group O appear to be more prone to develop peptic ulcers than those with other blood groups. Genetic influences appear to have greater role in duodenal ulcers as evidenced by occurrence in families, monozygotic twins and association with HLA-B5 antigen

Hormonal factors

Secretion of certain hormones by tumours is associated with peptic ulceration e.g. elaboration of gastrin by islet-cell tumour in zollinger-ellison syndrome syndrome, endocrine secretion in hyperplasia and adenomas of parathyroid glands, adrenal, cortex and anterior pituitary

Miscellaneous

Duodenal ulcers have been observed to occur in association with various other conditions such as alcoholic cirrhosis chronic renal failure, hyperparathyroidism, chronic obstructive pulmonary disease, and chronic pancreatitis

Endogenous mediators

Several endogenous mediators or substance have been identified and reported to be involved in the induction of gastrointestinal lesions. These have been found to be including lipid metaboliter, neuropeptides, amines, reactive oxygen species and free radicals (Elasbech and Weiss., 1988).

Platelet-Activating Factor (PAF)

PAF one of the most potent ulcerogen (Rosam et al.,1986). The mechanism involved, in PAF include ulceration is due to the sequestration of neutrophil aggregates in stomach, vasoconstriction, generation of free radicals and release of lysosomal enzymes (Mcmanus et al., 1980; Wallace and Whittle, 1986).

Thromboxcance A2(TXA2) and leukotriens(LTC4/D4)

They are derived from arachidonic acid through the action of enzymes cyclooxygenase(TXA2) and lipooxygenase (LTC4/D4). Vasoconstriction may be causapive factor in the TXA2 mediated gastric mucosal ulceration which predispose the mucosa to disruption by local irritants. Leukotrienes induces vasoconstriction in the vascular bed in the rat submucosa that leads to tissue necrocsis in the stomach (Wallace and Whittle, 1985). Leukotrienes also stimulate pepsinogen secretion from gastric from gastric chief cell (FIORUCCI et al., 1995). Involvement of leukotrienes in stress induced (Ogle and Cho, 1989) and ethanol induced (Wallace et al., 1989) ulcer by decrease in blood flow and increase in reactive oxygen species (Peskar et al, 1991; Vaananen et al., 1992) as been reported.

Histamine

Histamine is present in large quantities, about 40 micrograms per wet weight, in the oxyntic mucosa of humans and other mammals (Reite, 1972; Trodl et al., 1975). Histamine as been found in the gastric wall and it is powerful stumilant for gastric secretion (Black et al., 1972). However, excessive release of histamine by histamine release or by injection of aqueous solution of histamine produces gastric and duodenal ulcer (Shayer, 1974). Histamine is involved in the other type of ulceration because blocking of histamine receptors prevents reserpine, steroid and NSAIDs induced gastric ulcer in human of experimental animals (Lau and Ogle, 1981). Histamine blockers such as reaitidine have been reported to prevent psychological stress-included gastric ulceration (Cho and Ogle,1978, 1979).

Serotonin (5-hydroxytryptamine, 5HT)

Over 90% endogenous 5-hydroxytryptamine is found in the gastrointestinal tract. 5-HT is stored in endocrine cells and enteric neurons in the gut. It is established that 5-HT processes ulcer producing properties. Serotonin has been shown to be involved in the ethanol and reserpine induce ulceration. These ulcerogens release 5-HT from gastric mucosa which causes reduction in gastric blood flow and mucus depletion.

Free radicals

Free radicals are defined as chemical species processing unpaired electrons in their outer orbit that generally very reactive. If free radicals react with a non radical, another free radical must be produced. This implication reflected continuously in cells either during phagocytosis or pathological conditions. The most important reactant in free radicals biochemistry in the aerobic cells is oxygen and its radical derivative O2- and OH, H2O2 and transition metals (Fe2+, Cu+ )(cheeseman and slater, 1993). Reduction of oxygen by the transfer of a single electron produces superoxide radicals

O2 + e - O2-

Superoxide radicals can react with nitritc oxide to generate peroxynitrite

O2- + NO - ONOO-

A two-electron reduction of oxygen yields H2O2 and is often generated in biological systems via the dismutation of superoxide.

H2O2 is not free radical but falls into the category of reactive oxygen species (ROS) that indicates not only oxygen free radicals but also non-radical oxygen derivatives that are involved in oxygen radical population. H2O2 is an important compound in free radical biochemistry because it can rather easily be broken-down particularly in the presence of transition metal ions, to produce that most reactive and damaging oxygen free radicals, the hydroxyl radical OH.

H2O2 + Fe2+ - OH + OH- + Fe3+

This ion catalysed (Fe2+) reaction is known as Fenton reaction. The non-catalysed Haber-Weise is the reaction of superoxide directly with H2O2.

O-2 + H2O2 - OH + OH- + O2

The spontaneous reaction is less likely in biological system due to low steady state and concentration of the reactants. The auto-oxidation of reduced transition metal can also generate superoxide

Fe2+ + O2 - Fe3+ + O2-

Cu2+ + O2 - Cu2+ + O2-

The hydroxyl radicals are capable of reversibly or irreversibly damaging compounds of all biochemical classes, including nucleic acid, protein, and free amino acids, lipids, lipoprotein, carbohydrates and connective tissue macromolecules. These species may have impact on such cell activities as membrane function, metabolism and gene expression. The role of oxygen derived free radicals has been demonstrated in acute and chronic ulceration (Del Saldato et al., 1985; Bast et al., 1991; Freeman and Crapo., 1982). Involvement of neutrophil in ulcer as been implicated in different models of gastrointestinal mucosal injury such as colitis, ischemia (Perry et al., 1986), reperfusion (Grisham et al., 1990) stress (Das et al., 1997) and ethanol (Mizui and Doteuchi., 1986) induced ischemia/reperfusion and ethanol induced injury to the gastric and intestinal mucosa are substantially ameliorated in neutropenic animals (Tepperman and Soper, 1994). It is also widely accepted that oxygen derived free radical result in the lipid preoxidation and damage of cellular membrane with the release of intracellular component e.g. lysosomal enzymes leading to further tissue damage.

Another hypothesis is that free radicals particularly OH cause degradation of hyaluronic acid, the principal compound of the epithetlial basement membrane, and thus promote mucosal damage, the body has an effective mechanism to prevent and neutralize the free radical induced damage. It is done by a set of endogenous antioxidant enzymes such as superoxides dismutase, glutathione peroxidase, glucose oxidase and catalase. They help in maintaining the balance between the reactive oxygen species generation and its eradication.

Gastric mucosal defense mechanism

Mucous bicarbonate barrier

Peptic ulcers are not solely induced by the offensive factor of the acid and pepsin but the break down of mucosal resistance is also considered as an important factor making the stomach susceptible for ulcer (Goel and Bhattacharya, 1991).

The entire surface of the gastric mucosa is covered by a continuous layer of mucus gel, which has a variable thickness of less than 500 µm (Allen at al., 1993). Both the surface mucus cells and the mucus neck cells in the upper part of the gland secrete mucus. The process of exocytosis releases mucus predominately. Mucus consist of about 71% by weight salt and other dialyzable components, 0.5-1% free protein and a similar quantum of carbohydrate rich glycoprotein and 95% or more water. The glycoprotein component of mucus is responsible for the characteristic viscous gel forming property, believed to be important for the functional role of mucus.

Mucus and bicarbonate secretion (Allen and Garner, 1980) complement each other and either if functioning in isolation can afford little protection. Secretion of alkali by surface epithelial cells into the unstirred mucus layer thereby forming a pH gradient offers better protection than alone (Williams and Turnberg, 1981). Recent studies suggest that vagal cholinergic stimulation and luminal acid control gastric bicasbonate transport into the mucus gel is termed as 'mucus-bicardonate barrier' offering gastroprotection against damaging factors (Wallace, 1992).

Gastric mucosal renewal and restitution

The proliferation of gastric plays an important role in mucosalprotection during normal state and following mucosal damage. After mucosal damage, the undifferentiated neck cells proliferate, towards the lumen and differentiate into surface epithelial cells. The proliferation of gastric mucosal cell is the intrinsic property to fight against any damage. Following extensive damage of the surface epithelial cells, repair occurs with in a few hours, through a process called restitution that is not due to cell proliferation. This restitution process is augmented by high bicarbonate concentration and PGs do not appear to be involved in restitution (Goel and Bhattacharya, 1991).

Epidermal Growth Factors (EGF)

EGF is the most studied growth factor found in abundance in human salivary glands, bruneers gland and pancreas. Considerable evidence the secretion of various growth into the gastrointestinal lumen(Konturek et al., 1984). The presence of EGF like immunoreactivity in human gastric secretion has been recently demonstrated (Konturek et al.,1981). Thus EGF is secreted in gastric, duodenal and possibly, in small intestinal secretion and involved in the pathogenesis and healing of gastroduodenal ulcers in humans.

Mucosal and submucosal Blood flow

Mucosal blood flow constituents an important line of mucosal defense. It play a vital role in protecting the mucosa by delivering oxygen, nutrients and bicarbonate to the cells and removing hydrogen ion that has penetrated that mucus-bicarbonate and epithelial barrier. Prostaglandins appear to be important in regulating mucosal blood flow because in NSAIDs induced ulcer decrease in gastric mucosal blood flow has been observed (Kitahora and Guth, 1987; Ioel and Bhattacharya, 1991).

Endogenous Prostaglandins

Prostaglandins (PGs) are synthesized in large amounts by the gastric and intestinal mucosa. The PGE and PGI series of PGs have been shown to protect the deeper mucosal cells from the experimental necrotic damage (Miller, 1983) and some studies also suggest that a deficiency in prostaglantin production may contribution to ulcer formation (Dajani, 1986).

PGs increase gastric mucosal blood flow, mucus and bicarbonate secretion strengthens the mucus bicarbonate barrier. Since PGs protects the gastric mucosa by influencing all aspects of cytoprotective mechanism. Any drug (NSAIDs) or abnormal physiological (Stress) or pathological (H.pylori) condition which inhibits prostaglandin biosynthesis. Is expected to cause gastric damage (Goel and bhattacharya, 1991).

Sulphydryl compounds (SC)

Non protein sulpydryl compounds are present in high concentration in the gastric epithelium. The major component of SC is reduced glutathione (Karmeli et al., 1996) which is capable of binding to reactive free radicals which are generated during tissue ischemia and injury induced by noxious agent like enthanol (Avila et al., 1996). The precise role of SC in gasrtoduodenal cytoprotection remains unclear, but they appear to be involved that the blocking agent can reduce the cytoprotection effect of PGs in stomach (Karmeli et al., 1996).

Endogenous Antioxidants

Antioxidants are defined as "any substance that even when present at low concentration compared with those of an oxidizable substrate, significantly delays os prevent oxidation of that substrate". Uncontrolled oxidation in aerobic organisms produces oxidative stress, cell damage and eventually cell death.

These free radical scavenging enzymes are first line defense against oxidative injury with in the cell and are known as preventive antioxidants. They remove the reactants involved in inhidition of the free chain reaction (Buettner, 1993).

Many plant secondary metabolites act as potent antioxidants. Natural antioxidant defense have shown that the free radical scavenger/antioxidant such as SOD, catalase, vitamin E, vitamin C, vitamin A, Glutathione reduce the mucosal injury induced by different mediators (Sharma and Guptha, 1997).

Nitric Oxide (NO)

It is well reported that NO formed by constitute enzyme plays an important role in the modulation of gastric mucosal integrity by interacting with sensory neuropeptides and endogenous prostaglandins (Takeuchi et al., 1995).

Nitric oxide also inhibits the pentagastrin induced acid secretion in rates (Eaplugues et al., 1993). Musin secretion by rate gastric cells has been found to be stimulated by nitric oxide and c-GMP.

Treatment of Ulcer

Antacids

Antacids are now described mainly for symptomatic relief and widely accepted for self-medication. They are used to produce relief to the gastric pain associated with hyperchlorhydria (Berstad, 1982) the majority of antacids are based on combination of calcium, Aluminum and Magnesium all of which cause side effects. At low dose antacid are ineffective in neutralizing acid in the stomach. Extremely high doses of antacids are required to completely neutralize the excess acid in stomach (Ippoleti et al.,1983) the clinical status of antacid is in of flux-(Kumar et al.,1984). However, long term uses of these antacids have been shown to produce significant mucosal protection (Goel and Bhattacharya, 1991).

Antacids are used in combination to give both immediate and sustained action, to minimize undesirable effects by using a lower dose of each components, and to use one component to antagonize side effects of another (e.g. laxation verses constitation). The most common combination is that of Al (OH)3 and Mg (OH)2.

Histamine h2-receptor Antagonist

The introduction of H2-receptor antagonist in the mid 1972s by black and his colleagues constituted a major breakthrough in the drug treatment of peptic ulcers. H2-recptor antagonists can competitively inhibit histamine action at all H2-receptor but their clinical use is as inhibitors of gastric acid secretion (Feldman and Burton, 1990). H2-receptor antagonist also decreases gastric volume and pepsin concentration in the gastric content. H2-receptor antagonist inhibits gastric acid secretion elicited by histamine or by gastrin in a dose dependent and competitive manner. These agents decrease both basal and food stimulated acid secretion by 90% or more. H2-receptor antagonist also decreases intrinsic factor secretion from parietal cells (Lundell, 1975). The most commonly used drugs are cimetidine (Shrees and Roberts, 1981) and ranitidine (Woodings et al., 1980). Newer H2-receptor antagonist, such as nizatidine, and famotidine (Langtry et al., 1989)are also available. Recently roxatidine, loxatidine, has been shown to be devoid of such adverse effects and more potent and longer acting.

Ranitidine is a histamine H2-receptor antagonist that inhibits stomach acid production. It is commonly used in the treatment of peptic ulcer disease (PUD) and gastroesophageal reflex disease (GERD). It is currently marketed over the counter under the trade name zinetac and zantac by glaxosmithkline and by many other companies under varies other names.

Muscarinic antagonists

Muscarinic antagonists reduce basal secretion of gastric acid by 40-50% however; stimulated secretion is inhibited to a lesser extent. Vagal stimulation produces an increased secretion of histamine and gastric acid that can be blocked by either nicotine or muscarinic antagonist (pirenzepine) (Del-Tacca et al.,1989). Moreover, cholinergic agonist can excert powerful stimulatory effects on acid secretion in presebce of H2-antagonist through interaction with muscarinic receptor on the parietal cells. Selective antagonists of M1 receptor are as effective as atropine or other nonselective muscarinic antagonists, but they are likely to produce the adverse effects that are characteristic of aholinergic blockade (e.g. dry mouth, tachycardia). Two such drugs currently in clinical trail in the United States are pirenzepine and telenzepine.

The potent blocking effects of pirenzepine are unexplained because the type of muscarinic receptor on the endocrine cells has not been defined and pirenzepine is less effective than cimetidine in reducing acid secretion.

Proton pump inhibitors

The ultimate mediators of acid secretion are the H+-K+ATPase enzyme (proton pump) found in the smooth membrane structure in the parietal cell called tubule-vesicles as long as the cell is not secreting acid. As acid secretion increases, it transfers progressively to the microvilli of the secretry canaliculus of the cell. This transformation is due to change in level of c-AMP or (Ca2+) in the cell. H+-K+ATPase consist of a and b-subunits. The a-subunit is 1034 amino acid consisting catalytic subunit with a molecular mass os 114 KDa. A-subunit contains the phosphorylation site, ATP binding site and binding site for proton pump inhibitor. The 291 aminoacids containing b-subunit is glycoprotein with a molecular mass of 60-80 KDa. One of the roles of b-subunit is to stabilize the a-subunit in the membrane (Sachs and Shin, 1995).

A strict relationship between inhibition of acid secretion and block of H+-K+ATPase by omepazole has also been demonstrated. The mechanism of inhibition has also been extensively studied. The inhibition is due to irreversible interaction of the active compound with the SH group of H+-K+ATPase forming a disulphide bond (Im et al., 1985). Similar to omeprazole other substituted benzimidazole such as timoprazole and picoprazole also inhibit acid secretion (Sewing, 1984). Their efficacy and mechanism of action have been studied, but omeprazole was found to be more potent than other two compounds. Reported side effects include headache, diarrhea, skin rash and reversible abnormalities in biochemical liver function tests.

The long term use of omeprazole results in complete inhibition of H+-K+ATPase enzyme. Omeprazole produces gastric carcinoma when give long-term, probably due to complete acid inhibition which stimulates gastrin production causing hyperplasia (Larsson et al.,1986). Prolonged treatmenet with in patients omeprazole results in achlorhydria (blocked in acid seretion) and hypergastrenemia (lamberts et al., 1993).

Cytoprotective drugs

Misoprostol and Enprostil

PGE2 and PGI2, the predominant prostaglandins synthesized by the gastric mucosa, inhibit the secretion of acid and stimulate the secretion of mucus and bicarbonate. Misoprostol (analog of PGE1) inhibit gastric acid secretion by inhibiting the histamine- mediated stimulation of the paristal cell. Currently misoprostol is used to orevent gastric ulceration in patients who use large doses of Aspiring-like drugs for the treatment of arthritis (Roth et al., 1989; Penney 1989; Penney et al., 1994). Effective oral doses of misoprotol and related agents cause diarrhea and some abdominal cramping. Misoprostol and enprostil cause abdominal pain and diarrhea as well as bleeding in the first trimester of pregnancy (Levis et al., 1992).

Sucralfate

it was reported by nagashima and yoshida (1979). This drug is clinically effective in healing of gastric and duodenal ulcers and as no systemic side effects. Sucralfate is also effective is a prophylactic treatment, preventing peptic ulcer recurrence and preventing stress ulceration in critically ill patients. Sucralfate is a complex of aluminum hydroxide and sulphate sucrose which promote healing of ulcers (Libeskind, 1982;). It is thought to be act by coating the ulcer surface, by hinding to the positively charged exposed protein molecules. Sucralfate a nonabsorbable aluminum salt os sucrose octasulfate, served as reference compound. The drug sucralfate is claimed to inhibit peptic activity. It has got specific affinity for ulcer and protects the ulcer as natural mucus dose (Lichtenberger, 1983).

Tripotassium dicitrato bismuthate

It has been used clinically in duodenal refactory to cimetidine. Unfoutunately it is uncertain how it works. Although it does adhere to the raw surface of an ulcer (Koo et al., 1982), this 'Band-Acid' action seems unlikely to protect from acid and peptic attack. Under the influence of bismuth, the microvilli os epithelium cell in the duodenal mucosa return to their normal height whereas cimetidine has no such action. It is bismuth chelate which promotes the healing of peptic ulcers. It is possible that bismuth has a role on the maintenance of mucosal repair and a short cource of treatment may provide depot of bismuth, which gives some months of protection against relapse (Pounder, 1984). It may act by coating the ulcer and protecting the ulcer and protecting it in particular it absorbs pepsin. It also acts as bacterial against H.pylori.

Deglyrrhizinizes Liquorice (DGL) and carbenoxolone

DGL differs from pure liquorice-containing products and indeed, carbenoxolone in having a sufficiently low glycyrrhizinic acid content to render it free of the potential side-effects of carbenoxolone. The evidence for a beneficial effect of maintenance carbenoxolone is weak. In addition, in the latter study, hypertension and hypokalaemia were found in 27% and 15% respectively in patients over the age of 60.