Gastric acid secretion and peptic ulcer disease

Editor's Notes

1. The stomach consists of three anatomic (fundus, corpus or body, and antrum) and two functional (oxyntic and pyloric gland) areas. The hallmark of the oxyntic gland area is the parietal cell. The hallmark of the pyloric gland area is the G or gastrin cell.
2. The effects of drugs of the same pharmacological group are mostly ‘class’ or ‘group’ effectsThus all statins would have similar clinical usefulness, & all ACE inhibitors would be equally useful in management of HTN.It is not scientifically valid to assume that this is always the case.For instance, it was necessary to withdraw cerivastatin from the market because of a greater frequency of rhabdomyolysis,which was detected only during postmarketing surveillance, & it has recently been suggested that the effect of ramipril on mortality inheart failure might be greater than that of other ACE inhibitors. Scientifically valid conclusions should be based on head-to-head comparative trials between the various drugs. However, as thedemonstration of differences may be quite expensive (long-term trials with large study populations), smaller studies are usually carried out, the clinical relevance of which is quite debatable. Even more to the point: all too often, equivalence studies are accepted as valid while being methodologically clearly inadequate.The concept of bioequivalence is important because these drugs are highly labile in an acid environment and are rapidly degraded ifreleased in the stomach. the effect of a given preparation depends, not only on the amount of the active molecule contained in the capsule or tablet, but at least as much on the quality and stability of the enteric coating protecting the active molecule.The potency of these bioequivalence studies is all too often debatable.
3. Administration in divided doses seems to be more effective than a single daily dose. Thus one study has shown that the same daily dose of omeprazole, administered in two divided doses (2 X 20mg), achieves a slightly better control of acid secretion than is obtainedwith single-dose administration (1 X 40mg).However, therapeutic compliance will be much more difficult to achieve in the case of divided dosage, and there are no comparative clinical studies that may allow conclusions as to whether the difference in control of gastric secretion is really relevant with respect to the therapeutic effect.
4. The success of these drugs, with sales totalling $13.6 billion worldwide in 2009, is not just a result of their potency and effectivenessin improving symptoms and complications of acid-peptic disease. Their safety among pharmacologic agents has been unparalleled.Clopidogrel:on November 17, 2009, the US Food and Drug Administration (FDA) issued an alert to health care professionals and thepublic about the potential interaction between clopidogrel and omeprazole. In this alert, the FDA stated that the use of omeprazoleor esomeprazole (Nexium) with clopidogrel should be avoided.To date, only one prospective randomized controlled trial has specifically investigated the effect of PPIs on cardiovascular outcomesin patients using clopidogrel (Cogent trial). The study ended prematurely, when the sponsor suddenly and unexpectedly lost its financialBacking. Osteoporosis & fractures: Even though the studies had methodologic limitations, on May 25, 2010, the FDA announced a change in the required labeling information for PPIs to indicate a possible risk of fracture with these drugs.Acute interstitial nephritis: A systematic review from 2007 found 64 cases documented in the literature, 12 of which were considered certainly associated, and 9 of which were probably associated.
5. In the past two years some scientific evidences have suggested a possible negative interference of PPIs on antiplatelet effect of clopidogrel because of the competitive inhibition of the CYP 2C19 isoenzyme.
6. Barry J. Marshall receiving his Nobel Prize from His Majesty the King Carl XVI Gustaf of Sweden at the Stockholm Concert Hall, 10 December 2005.
7. Serological test: serological tests are not all equivalent. Only validated IgG serology tests should be used owing to variability in the accuracy of different commercial tests.Validated IgG serology may be used in setting of recent use of antimicrobial* and antisecretory drugs, or ulcer bleeding, atrophy and gastric malignancies.Fecal antigen test:Not often used despite its high sensitivity and specificity before and after treatment.Should have a more prominent place, as it is inexpensive and noninvasive.PCR: Sensitive and specific – Not standardized.Finger-stick serology testVery poor and cannot be equated with ELISA serology
8. On considère que la masse bactérienne revient à sa valeur initiale en un mois.Au cas où le malade ne pourrait arrêter son traitement antisécrétoire, la prise de pansements gastriques qui n’ont pas ces conséquences peut être envisagée.
9. Rapid urease tests. Another indirect test for Helicobacter pylori, the rapid urease test, is based on metabolism of urea by urease. In this test, a mucosal biopsy is inoculated into a well that contains urea and a pH-sensitive dye (phenol red). If urease is present in the biopsy, urea in the medium is converted to NH4+, which will raise the pH. In response to an elevation in pH, the pH sensitive dye causes the well to change colors. This figure is an example of a rapid urease test, the CLOtestTM (Delta West Limited, Bentley, Western Australia). In this test, presence of H. pylori in a mucosal biopsy will be evidenced by a color change from yellow to red.
10. High-dose PPIs increase cure rates by around 6 – 10% in comparison with standard doses.Increasing dose of PPI from, for example, 20 mg omeprazole twice daily to 40 mg of esomeprazole or rabeprazole twice daily may increase cure rates by 8 – 12%.Extending duration of triple therapy from 7 to 10 – 14 days improves eradication success by approximately 5% and may be considered.Penicillin allergyIn patients with penicillin allergy, in areas of low clarithromycin resistance, for a first-line treatment, a PPI-clarithromycin-metronidazole combination may be prescribed and in areas of high clarithromycin resistance, the bismuth containing quadruple therapy should be preferred.As a rescue regimen, in areas of low fluoroquinolone resistance, a levofloxacin containing regimen (together with a PPI and clarithromycin) represents a second-line alternative in the presence of penicillin allergy.
11. treatment success fails to reach even 80% in most studies in the southern and central European countries of France, Italy, Spain and Turkey, populations which, as the Maastricht III report noted, tend to have a high prevalence (~18.5%) of clarithromycin resistance.triple therapy with a PPi, amoxicillin and clarithromycin should be avoided.
12. We have observed that using a combination of both metronidazole and clarithromycinin quadruple regimens is very effective at eradicating strains of H pylori resistant to either clarithromycin or metronidazole. In fact, only a negligible reduction in efficacy was observed when concomitant quadruple regimens containing a PPI, amoxicillin, clarithromycin and metronidazole (a nitroimidazole), were given to patients with either nitromidazole- or clarithromycin-resistant H pylori.
13. Widespread acceptance of this regimen was not forthcoming, possibly related to the requirement for dosing three or preferably four times daily, the administration of a large number of pills, a lack of availability of bismuth in many areas, and perhaps most importantly, untilrecently, the absence of a pharmaceutical sponsor to assist in education and marketing of the regimen.Capsule containing bismuth subcitrate (140 mg), metronidazole (125 mg), and tetracycline (125 mg) is available and FDA approved. The dosing is three capsules four times daily plus a PPI twice daily.
14. On considère que la masse bactérienne revient à sa valeur initiale en un mois.Au cas où le malade ne pourrait arrêter son traitement antisécrétoire, la prise de pansements gastriques qui n’ont pas ces conséquences peut être envisagée.
15. Antibiotic combination should be chosen according to local H pylori antibiotic resistance patterns.
16. Cox-1 Inhibition:Decreased mucosal PGs synthesisDecreased of mucosal blood flow (+++).Cox-2 Inhibition:Increased neutrophils adherent to vascular epithelium Important factor of ulcer developmentTopical Irritation:Acidic NSAIDs exerts topical irritant effects leading to epithelial injury.Suppression of COX-1 causes a profound reduction of mucosal prostaglandin synthesis which probably impairs many components of mucosal defence. Among these, the reduction of mucosal blood flow may be most important. Suppression of COX-2 leads to an increase in the number of neutrophils adhering to the vascular endothelium in the gastrointestinal microcirculation, which has been shown to be an important factor in ulcer development. Many NSAIDs, particularly acidic ones, also exert topical irritant eff€ects on the mucosa, leading to epithelial injury.
17. Aspirin tablet coated with a combination of cellulose, silicon, or other inactive ingredients has resistance to disintegration in the stomach; this property allows dissolution of the drug in the more neutral to alkaline environment of the duodenum.safety of this type of product has been confirmed by several endoscopic studies that compared enteric-coated with plain aspirinpreparations in healthy volunteers with less gastric erosion and microbleeding in those who used the enteric-coated preparation.Buffering agents (calcium carbonate, magnesium oxide, and magnesium carbonate) lower hydrogen ion concentration in themicroenvironment of aspirin particles; this results in increased gastrointestinal solubility of aspirin, and reduced contact time between aspirin particles and the gastric mucosa. The expectation that buffering would reduce gastric damage has been largely unsupported by endoscopic studies. Although buffered preparations are better tolerated by some patients.Use of low doses of enteric-coated or buffered aspirin carries a three-fold increase in the risk of major UGIB. The assumption that these formulations are less harmful than plain aspirin may be mistaken.
18. Pre-endoscopic administration of PPIs in patients with nonvariceal upper GI bleeding is still of controversial efficacy.The optimal dose and route of PPI administration has yet to be determined.
19. RebleedingThe reduction of 30-day rebleeding rates remained statistically significant in all predetermined subgroup analyses. That is, PPIs significantly reduced rebleeding independent of methodological quality of the trials, severity of baseline endoscopic signs of recent hemorrhage, type of control treatment (placebo or H2RA), geographic location of the trials (conducted in Asia or elsewhere), mode of PPI administration (oral or intravenous), dose of PPI (high-dose defined as at least 80 mg bolus followed by an intravenous infusion of 8 mg/h for 72 hours; low-dose defined as any lesser dose intravenous or oral), and whether or not endoscopic hemostatic treatment was given.Other outcomes:Surgical interventions were significantly less common with PPI treatment (6.1%) than with control treatment (9.3%); OR 0.61, 95% CI 0.48–0.78; NNT 34, 95% CI 20–50. Further endoscopic hemostatic treatment (after randomization) was also reduced with PPIs (5.6%) compared with control treatment (15.7%); OR 0.32, 95% CI0.20–0.51; NNT 10, 95% CI 8–17.MortalityDespite the beneficial effect of PPI treatment on the above outcomes, there was no evidence of an effect on all-cause mortality rates (OR 1.01, 95% CI 0.74–1.40). PPIs significantly reduced mortality among trials that had been conducted in Asia (OR 0.35, 95% CI 0.16–0.74; NNT 34, 95% CI 20–100), but had no verifiable effect among trials that had been conducted elsewhere (OR 1.36, 95% CI 0.94–1.96). Similarly to the outcome of rebleeding, a higher treatment effect of PPIs in Asian trials was confirmed by metaregression.There have been three other published meta-analyses of RCTs that have assessed the role of PPIs in peptic ulcer bleeding. The most consistent finding of these meta-analyses, which is also in agreement with the Cochrane meta-analysis, is that PPIs compared with H2RAs or placebo significantly reduce rebleeding rates in patients with peptic ulcer bleeding.
20. Peptic ulcer can also penetrate into adjacent organs, especially with a posterior DU, which can penetrate into the pancreas, colon, liver, orbiliary tree.
21. Retained antrum syndrome is a rare form of hypergastrinemia in patients who have had a Billroth II operation.If a small cuff of antrum remains in the afferent limb and is excluded from exposure to gastric acid, the gastrin-producing G cells willrelease gastrin without control by the negative feedback loop, leading to hypersecretion of acid in the remaining stump.