OMEPRAZOLE is the first of a new class of drugs that inhibit gastric secretion by altering the activity of H+/K+ATPase,1 2 3 the

final common step of acid secretion, in gastric parietal cells. The discovery of omeprazole has led to new insights into the mechanism of gastric secretion, knowledge of the genesis of certain gastrointestinal tumors, and the development of new treatments for acid-peptic diseases. In the United States, omeprazole has been approved only for short-term use in certain patients with reflux esophagitis and for patients with the ZollingerEllison syndrome, because of concerns raised by the results of long-term studies of toxicity in animals, but in many countries the approved uses are much wider. This review will discuss the pharmacologic features of omeprazole and the results of trials of the drug in patients with duodenal ulcer, gastric ulcer, reflux esophagitis, and the ZollingerEllison syndrome.

Pharmacology Gastric Acid Secretion, H+/K+ATPase, and the Action of Omeprazole

The secretion of hydrochloric acid by gastric parietal cells ultimately depends on the function of the proton (hydrogen ion) pump.1 , 2 This pump is H+/K+ATPase, a membrane-spanning enzyme that uses the energy released by the metabolism of ATP to move protons (actually, hydronium ions) across the membrane in exchange for potassium ions4,5 (Fig. 1Figure 1

Schematic Diagram of the Action of Omeprazole on a Gastric Parietal Cell.). H+/K+ATPase consists of two subunits: the 111,000-dalton subunit, which catalyzes the hydrolysis of ATP and transports ions, and the smaller subunit, whose function is unknown. In the nonsecreting state, H+/K+ATPase is situated in vesicles in the cell cytoplasm. Since the vesicles contain no potassium and the vesicular membranes are impermeable to potassium ions, the pump is inactive.4 , 5 On activation of parietal cells by the appropriate stimulus, such as histamine, the H+/K+ATPase translocates to the plasma membrane of the secretory canaliculus of the parietal cell.6 , 7 The extracellular aspect of H+/K-ATPase is thus exposed to potassium ions, and because there is an associated increase in the permeability of the membrane to potassium,5 the cells are able to secrete acid at a pH of about 1.0. Omeprazole has been shown in several species to inhibit acid secretion by inhibiting H+/K+ATPase.8 9 10 Omeprazole is a lipophilic, weak base with a pK of 4.0. It is absorbed in the intestine and reaches the parietal cells of the stomach through the bloodstream. At a pH of approximately 7 omeprazole is not charged and can cross cell membranes (Fig. 1). However, in the secretory canaliculus of actively secreting gastric parietal cells, where the drug is exposed to a pH of less than 2.0, omeprazole becomes protonated. It therefore ceases to be lipophilic and is trapped and concentrated. Omeprazole itself is inactive, but under acidic conditions it is converted to the active form, a sulfenamide11 , 12 that reacts covalently with the sulfhydryl groups of cysteine residues on the extracellular surface of the subunit H+/K+ATPase and inhibits the activity of the enzyme (Fig. 1). The resumption of acid secretion after the administration of omeprazole almost certainly requires synthesis of new H+/K+ATPase protein.13 The half-life of H+/K+ ATPase is approximately 18 hours.

Pharmacokinetics and Pharmacodynamics

Exposure to gastric acid degrades omeprazole and leads to poor oral bioavailability.14 The drug has therefore been formulated in pH-sensitive granules that release omeprazole only when the pH is above 6. With this formulation the bioavailability of omeprazole is about 50 percent.14 Peak plasma concentrations occur two to four hours after oral administration15 and tend to increase during the first few days of treatment, probably because the increasing inhibition of gastric acid secretion results in less degradation of omeprazole in the gastric lumen. The plasma half-life of omeprazole is about 60 minutes,16 but because it is linked covalently to H+/K+ ATPase, the duration of action of a single dose exceeds 24 hours.17 The degree of inhibition of acid secretion thus does not correlate with the plasma concentration of the drug, but it does correlate with the area under the plasma concentrationtime curve.18 A single 20-mg dose of omeprazole inhibits acid secretion by 65 percent after 4 to 6 hours and by 25 percent after 24 hours,18 but with subsequent doses inhibition increases, reaching a plateau after four doses.18 This increased activity is due both to increased bioavailability and to inhibition of more H+/K+ ATPase molecules. The steady-state inhibition of acid secretion during treatment with 20 mg of omeprazole per day varies widely from person to person: ranges of 35 to 65 percent, based on measurements of acid secretion 24 hours after drug administration,18 19 20 and 30 to 100 percent, based on measurements of 24-hour gastric acidity determined by intragastric pH,21 , 22 have been reported. Indeed, in some subjects 150 mg of ranitidine twice a day inhibited gastric acidity more effectively over a 24-hour period than 20 mg of omeprazole a day. With larger doses of omeprazole, variation between patients diminishes and acid secretion is inhibited more profoundly.18 , 21 When treatment is stopped, it takes at least three days for acid secretion to return to pretreatment levels.18 , 21 Rebound hypersecretion does not occur.21 , 23

Metabolism
Two major metabolites of omeprazole found in plasma are the sulfone derivative and hydroxyomeprazole.16 Neither inhibits the secretion of gastric acid,14 15 16 and both are further metabolized before being excreted. Eighty percent of the metabolites is excreted in the urine, and the other 20 percent is excreted in the feces after biliary secretion. Because omeprazole is extensively metabolized by the hepatic cytochrome P-450 system, interactions with other drugs may occur (see below). The pharmacokinetics of omeprazole are not altered in patients with impaired renal function,24 , 25 but in elderly patients16 and those with impaired liver function,16 , 26 metabolism of the drug is slower and bioavailability is greater than in control subjects.16 However, no dose adjustment is required.

Other Actions of Omeprazole

Omeprazole does not inhibit the secretion of intrinsic factor,27 , 28 and the absorption of crystalline vitamin B12 is normal.28 The absorption of vitamin B12 that is bound to protein is decreased,29 but long-term omeprazole therapy does not appear to cause vitamin B12 deficiency. Omeprazole reduces the secretion of pepsinogen slightly,20 , 27 probably because it decreases gastric acidity and volume, and serum pepsinogen concentrations rise during omeprazole therapy.20 Omeprazole has no effect on esophageal pressures30 or gastric emptying.31 Enzymes

similar to gastric H+/K+ATPase may exist in the colon and the kidney,32 but since such enzymes are not in an acidic environment, omeprazole is not trapped or activated at these sites. Because the release of gastrin by antral G cells is inhibited by a fall in gastric pH and stimulated by an increase in pH,33 any drug capable of profoundly inhibiting gastric acid secretion should lead to an increase in plasma gastrin concentrations. Rats repeatedly given large doses of omeprazole had increased plasma gastrin concentrations,34 an increase in gastrinimmunostaining of antral G cells, and a reduction in somatostatin immunostaining of D cells.35 , 36 More importantly, in the initial two-year toxicity studies, administration of omeprazole to rats (but not mice) resulted in carcinoid tumors of the body of the stomach and hyperplasia of certain oxyntic mucosal endocrine cells, the enterochromaffin-like cells.37 The carcinoid tumors occurred more frequently in female rats given four different doses of omeprazole; they developed in 2 percent of rats given 1.7 mg of omeprazole per kilogram of body weight per day and in 40 percent of those given 140 mg per kilogram per day.37 Tumors did not develop in any of the control rats. These results led the Food and Drug Administration to restrict the length of omeprazole treatment to eight weeks, except in patients with the ZollingerEllison syndrome. Extensive work has since been performed to elucidate the mechanism by which omeprazole causes these changes in rats. There was a close correlation between omeprazole-induced hypergastrinemia and hyperplasia of enterochromaffin-like cells, and these changes were reversible after administration of the drug for as long as one year.35 36 37 38 39 Antrectomy abolished omeprazole-induced hypergastrinemia and hyperplasia of enterochromaffin-like cells,36 whereas intravenous infusions of gastrin for four weeks produced hyperplasia of enterochromaffin-like cells.40 Other studies have shown that a variety of drugs that inhibit gastric acid secretion can induce hypergastrinemia, hyperplasia of enterochromaffin-like cells, and gastric carcinoid tumors in rats. They include the H2-receptor antagonists ranitidine41 and loxtidine,42 and ciprofibrate and related hypolipidemic compounds43 that inhibit the secretion of acid by an unknown mechanism. Furthermore, in untreated rats subjected to a 75 percent fundectomy, hyperchlorhydria occurs, with the consequent development of hypergastrinemia, enterochromaffin-like-cell hyperplasia, and gastric carcinoid tumors.44 On the basis of these studies, most45 , 46 but not all47 investigators believe that omeprazole is not a direct carcinogen in rats, but causes gastric carcinoid tumors through its ability to inhibit the secretion of gastric acid and so cause hypergastrinemia, and it is the latter that stimulates tumor formation. The occurrence and possible risks of omeprazole-induced hypergastrinemia in humans are discussed in the section on side effects.

Omeprazole in Acid-Peptic Diseases Duodenal Ulcer

Several early studies examined the efficacy of various oral doses of omeprazole on the healing of duodenal ulcer and relief of ulcer symptoms.48 49 50 51 52 53 54 55 56 57 58 59 Two weeks of treatment with 10 mg per day of omeprazole produced healing rates of 50 percent, and the respective healing rates with doses of 20, 30, 40, and 60 mg per day were 63 to 79 percent, 73 to 88 percent, 93 percent, and 57 to 100 percent. After four weeks, all doses of more than 10 mg per day resulted in rates of healing of 90 to 100 percent. Therefore, a dose of 20 mg per day was used in most subsequent studies. All doses produced rapid relief of symptoms.

At least 16 randomized, controlled trials of omeprazole and H2-receptor antagonists have been performed.60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 After two weeks of therapy ulcers healed in 42 to 83 percent of the patients treated with 20 mg of omeprazole per day and in 34 to 65 percent of those given 300 mg of ranitidine per day a therapeutic advantage for omeprazole of 2 to +30 percent in individual studies. After four weeks the ulcer healed in 82 to 97 percent of the patients given omeprazole and in 63 to 96 percent of those given ranitidine, a therapeutic advantage for omeprazole of 5 to +19 percent. The results of a meta-analysis76 that I performed indicate that the pooled difference in healing for the eight studies in which 20 mg of omeprazole per day or 300 mg of ranitidine per day was given for two weeks was 14.1 percent (95 percent confidence interval, 8.2 to 20.2), a significant advantage for omeprazole (Fig.

2Figure 2 Differences in the Rates of Healing of Duodenal Ulcers in Patients Treated with Omeprazole (O), Ranitidine (R), or Cimetidine (C), Expressed as Therapeutic Advantage for Omeprazole over the H2-Receptor Antagonists, after Two and Four Weeks of Therapy.). After four weeks the difference was smaller (8.7 percent) but still significant. With doses of omeprazole of more than 20 mg per day, there was a larger difference in favor of omeprazole (Fig. 2). In five studies in which the treatment lasted six to eight weeks,62 , 66 , 68 , 69 , 72 meta-analysis again demonstrated an advantage for omeprazole (pooled difference in healing, 5.9 percent; 95 percent confidence interval, 2.5 to 9.4). For both classes of drugs, the rate of healing was slower in smokers than in nonsmokers,61 , 65 , 72 , 74 , 75 and large ulcers healed more slowly than small ulcers.61 , 74 , 75 There were also geographic variations in healing rates: rates in patients from the United States71 and Canada69 were lower than those in patients from Hong Kong.65 Although both classes of drugs were effective in relieving symptoms, in 11 of the studies more patients taking omeprazole were free of symptoms after two weeks of therapy,60 , 61 , 65 , 66 , 68 69 70 71 72 73 74 and in 5 studies this difference was significant.60 , 61 , 65 , 66 , 68 , 71 In two other trials daytime pain was less frequent in patients taking omeprazole than in those taking ranitidine,67 , 74 and the patients treated with omeprazole took significantly less antacid in three of six trials.62 , 67 , 69 , 70 , 73 , 75 In five open studies of a total of 88 patients with resistant duodenal ulcers those that had not healed after at least two months of treatment with an H2receptor antagonist in standard or high doses77 78 79 80 81 82 40 mg of omeprazole per day produced healing in 98 percent in four to eight weeks. In a randomized comparative trial,83 119 patients with ulcers (88 percent of which were duodenal) resistant to conventional therapy received 40 mg of omeprazole per day or continued taking an H2-receptor antagonist. After eight weeks ulcers had healed in 98 percent of the former and 60 percent of the latter (P<0.001). However, in a double-blind trial of patients whose ulcers had not healed after six weeks of treatment with H2-receptor antagonists, treatment with 20 mg of omeprazole per day or 150 mg of ranitidine twice a day for eight weeks resulted in healing in 80 percent of the patients in each group.84 Thus, in the only study of patients with resistant ulcers that did not demonstrate an advantage for omeprazole, the daily dose was 20 mg rather than 40 mg.

In patients with duodenal ulcers that heal after treatment with H2-receptor antagonists, the relapse rates are 50 to 60 percent for the first six months.85 , 86 After omeprazole therapy was stopped, ulcers recurred in 41 to 44 percent of patients after 6 months49 , 52 , 87 and in 88 percent after 12 months.88 In one of four comparative trials the relapse rate after eight weeks was lower in patients who had received omeprazole,66 but in the three other studies the sixmonth relapse rates were similar (41 to 72 percent) for omeprazole and H2-receptor antagonists.60 , 62 , 72 Taken together, the results of omeprazole therapy in patients with duodenal ulcer indicate that a dose of 20 mg of omeprazole per day produces more rapid healing than standard doses of H2-receptor antagonists, but the longer treatment is continued the smaller the difference between the treatments. For patients with resistant ulcers, 40 mg of omeprazole per day is usually effective, but the rate of relapse after discontinuation of therapy is similar to that after discontinuation of H2-receptor antagonists. These results are consistent with the thesis that the major determinants of the healing of duodenal ulcers are the degree of acid inhibition and the duration of therapy.89

Gastric Ulcer
Early noncomparative studies demonstrated that gastric ulcers healed in 22 to 27 percent of patients treated with 30 mg of omeprazole per day for two weeks. The rate of healing in patients treated for four weeks was 69 to 72 percent, and in those treated for six to eight weeks it was 92 to 100 percent.90 , 94 In one study 40 mg of omeprazole per day resulted in a higher rate of healing than 30 mg per day after four weeks, but the rates were similar after treatment for six weeks.92 Various doses of omeprazole and H2-receptor antagonists have been compared in randomized, controlled trials. In patients with ulcers of the gastric body and antrum93 94 95 96 97 or prepyloric ulcers,98 both types of drug were effective: ulcers healed in 86 to 96 percent of patients treated for six to eight weeks with omeprazole and in 78 to 90 percent of those treated with an H2-receptor antagonist. Meta-analysis revealed that when the DerSimonian and Laird analysis was used, 20 mg of omeprazole per day was significantly more effective than H2receptor antagonists only after eight weeks, and that 30 to 40 mg of omeprazole was more

effective than H2-receptor antagonists only after four weeks (Fig. 3Figure 3 Differences in the Rates of Healing of Gastric Ulcers in Patients Treated with Omeprazole (O), Ranitidine (R), or Cimetidine (C), Expressed as Therapeutic Advantage for Omeprazole over the H2-Receptor Antagonists, after Four and Six to Eight Weeks of Therapy.). However, when the Peto method was used, all differences were significant. In all these studies, irrespective of the drug used, healing was slower in patients with large ulcers than in those with small ulcers, but the healing rate was reduced in smokers in only one study.95 Healing was faster in patients with prepyloric ulcers than in those with ulcers of the gastric body in one study93 but not in another.96 In one report the advantage of omeprazole over ranitidine was particularly marked in patients taking nonsteroidal antiinflammatory drugs concomitantly.96 In most trials there was no difference in symptomatic response, but in three trials more patients treated with omeprazole were free of symptoms after one to four weeks,95 , 96 , 98 and in one trial the patients treated with omeprazole consumed less antacid.95

Among 82 patients with gastric ulcers that had not healed after at least two months of treatment with an H2-receptor antagonist, therapy with 40 mg of omeprazole per day for eight weeks resulted in healing in 96 percent.77 , 79 , 82 , 83 Omeprazole was also effective in patients with resistant anastomotic ulcers.79 The rates of relapse of gastric ulcer after therapy was stopped in two comparative studies were 35 percent and 47 percent after six months, with no difference in the rates between patients treated with omeprazole and those given H2-receptor antagonists.96 , 97 , 99 Relapses were more likely in patients who had prepyloric ulcers or in smokers.97 , 99 Overall, the results indicate that the rates of healing of gastric ulcer are only slightly higher with omeprazole than with H2-receptor antagonists and the rates of relapse are similar. Thus, for most patients with gastric ulcers, omeprazole offers little or no advantage. For patients with resistant gastric ulcers, however, 40 mg of omeprazole a day appears to be more effective than continued treatment with H2-receptor antagonists.

Reflux Esophagitis
Only two dose-ranging studies of omeprazole have been performed in patients with esophagitis. In one, treatment with 30 mg of omeprazole per day resulted in healing in seven of eight patients after eight weeks.100 In a subsequent double-blind study, after four weeks the rates of healing with placebo and 20 and 40 mg of omeprazole per day were 6, 70, and 82 percent, respectively.101 These results compare favorably with healing rates of about 60 percent in patients treated with H2-receptor antagonists.102 Both doses of omeprazole were effective for symptom relief, but the 40-mg dose resolved symptoms in a larger percentage of patients. In randomized, controlled trials, esophagitis healed in 57 to 74 percent of patients after four weeks of omeprazole therapy and in 78 to 87 percent after eight weeks; the comparable values in patients treated with ranitidine were 27 to 43 percent and 28 to 56 percent.103 104 105 106 107

108 109 As shown in Figure 4Figure 4Differences in the Rates of Healing of Esophagitis in Patients Treated with Omeprazole (O), Ranitidine (R), or Cimetidine (C), Expressed as Therapeutic Advantage for Omeprazole over the H2-Receptor Antagonists, after Four and Eight Weeks of Therapy., meta-analysis demonstrated a significant therapeutic advantage of 35 to 40 percent in favor of omeprazole after both four and eight weeks of therapy. Esophagitis can be classified according to severity. A common classification defines Grade I esophagitis as mucosal erythema with or without friability, Grade II as superficial nonconfluent ulceration, Grade III as confluent ulceration, and Grade IV as extensive mucosal damage or stricture formation, shortening, or Barrett's esophagus. In studies that stratified patients according to grades of esophagitis, the advantage for omeprazole over H2-receptor antagonists after both four and eight weeks of treatment was slightly greater in the patients with more severe disease. Overall,

symptoms were completely relieved in 61 to 74 percent of the patients taking omeprazole and in 12 to 33 percent of the patients taking an H2-receptor antagonist. For relief of heartburn, the figures were 82 to 94 percent for omeprazole and 31 to 55 percent for the H2-receptor antagonists. All doses of omeprazole were more effective than H2-receptor antagonists in relieving symptoms, and in two studies the patients taking omeprazole required significantly less antacid.106 , 107 The efficacy of 40 mg of omeprazole per day in patients with esophagitis that had not improved after at least three months of treatment with large doses of H2-receptor antagonists has been described in open studies in a total of 175 patients.79 , 80 , 104 , 110 111 112 113 114 Included in these studies were many patients who had had major complications of esophagitis and had undergone esophageal surgery before the study began. Therapy with omeprazole for 4 to 12 weeks resulted in healing in 90 to 100 percent of the patients. In a double-blind comparative trial, 98 patients with resistant esophagitis received 40 mg of omeprazole per day or 300 mg of ranitidine twice a day for 12 weeks.115 The esophagitis healed in 90 percent of the patients receiving omeprazole and in 47 percent of those receiving ranitidine (P<0.001). Irrespective of whether the esophagitis healed during omeprazole101 , 106 or ranitidine106 therapy, relapse occurred soon after therapy was stopped: 60 percent of the patients relapsed after three months, and 80 to 90 percent after six months. However, in a group of patients with resistant esophagitis that healed after omeprazole therapy, who were given a maintenance dose of 20 mg per day, only 19 percent relapsed in six months.114 In contrast to the slight advantage of omeprazole for most patients with duodenal ulcer and the marginal advantage for patients with gastric ulcer, omeprazole is much more effective than H2receptor antagonists for the relief of symptoms and mucosal healing in patients with all grades of reflux esophagitis. In many patients it is the only drug capable of healing the mucosa. Because of the high rate of relapse, however, long-term therapy is required, and despite the success of omeprazole, the possible risks to the stomach of long-term treatment have made the management of chronic, severe esophagitis problematic (see below).

ZollingerEllison Syndrome
Patients with the ZollingerEllison syndrome have hypersecretion of gastric acid and require large doses of H2-receptor antagonists to reduce the secretion of acid to safe levels. Treatment with H2-receptor antagonists can prevent the consequences of hypersecretion of gastric acid, such as severe, complicated peptic ulceration, diarrhea, and malabsorption, but the doses must be large enough to reduce acid secretion to less than 10 meq per hour125 (or <5 meq per hour if the patient has severe esophagitis117 or has had a partial gastrectomy118). Nearly all patients require medication every six hours, and some need as much as 9600 mg of ranitidine per day.116 Omeprazole has been given to patients with the ZollingerEllison syndrome who were thought to be resistant to treatment with H2-receptor antagonists, although in most cases the dose of the drug had been insufficient. Omeprazole resolved the acid-related problems in nearly all patients,119 120 121 122 123 124 125 126 127 128 129 130 131 132 including those who, despite a reduction of acid secretion according to established criteria,116 117 118 still had symptoms or mucosal disease (including recurrent esophageal stricture). Lowering acid output

further with omeprazole produced prompt resolution.116 117 118 , 132 The doses of omeprazole used ranged from 20 mg per day to 120 mg three times a day. In patients in whom the dose was adjusted to reduce acid output to less than 10 meq per hour, the median daily dose was about 80 mg.132 Although 120 mg given once daily did not control acid secretion in 25 percent of the patients, dividing the daily dose (60 mg every 12 hours) controlled the secretion of acid in every case.123 , 132 Some patients with the ZollingerEllison syndrome have taken omeprazole, often at a high dose, for more than five years. For patients with the ZollingerEllison syndrome omeprazole has an advantage over H2receptor antagonists fewer tablets and fewer doses are needed per day. In addition, fewer patients require increases in the dosage during long-term treatment,116 , 123 , 132 and in some patients omeprazole is the only drug that will resolve all symptoms and mucosal disease. Furthermore, omeprazole does not usually cause achlorhydria in these patients, and in more than four years of continuous administration has not resulted in increased plasma gastrin concentrations or changes in the gastric mucosa (see below). Omeprazole is now the drug of choice for patients with the ZollingerEllison syndrome.

Side Effects and Toxicity General Effects

More than 19,000 patients have been given omeprazole in clinical trials since 1983, but only patients with the ZollingerEllison syndrome and those with resistant acid-peptic disease have received omeprazole for longer than a few weeks. Nevertheless, the frequency of side effects due to omeprazole has been similar to that for placebo or H2-receptor antagonists,17 , 46 , 133 and there have been no consistent abnormalities in laboratory test results, including tests of thyroid and liver function. Although omeprazole has a minor inhibitory effect on the synthesis of adrenal steroids,134 it has no clinically important effect on adrenal or other endocrine function.133 Omeprazole interacts with the cytochrome P-450 system in the liver135 , 136 and inhibits the metabolism of some drugs (the R isomer of warfarin,137 phenytoin,138 , 139 diazepam,138 , 140 antipyrine,141 and aminopyrine141) but not others (propranolol,142 the S isomer of warfarin,137 and theophylline143). Since the elimination of phenytoin and warfarin is prolonged by omeprazole, patients taking these drugs concomitantly should be monitored closely. Although omeprazole has proved to be remarkably free of side effects, postmarketing surveillance will be important to confirm its safety profile.

Effects on the Stomach and Gastrin Secretion

The main issue concerning the safety of omeprazole has been its ability to produce hypergastrinemia and gastric carcinoid tumors in rats and the implications of these findings for humans. Chronic hypergastrinemia in humans can lead to hyperplasia of enterochromaffin-like cells and carcinoid tumors of the body of the stomach, although gastric carcinoid tumors associated with hypergastrinemia are rare144 145 146 and generally are of low malignancy.147 148 149 Patients with gastric atrophy and achlorhydria, whether or not they have pernicious anemia, have hypergastrinemia and hyperplasia of enterochromaffin-like cells, and gastric carcinoid tumors are found in approximately 5 percent.150 151 152 Whether in all cases these

are truly tumors or simply hyperplasia is questionable because there are several reports of the disappearance of gastric carcinoid tumors after antrectomy and the normalization of plasma gastrin concentrations in these patients.153 154 155 All patients with the ZollingerEllison syndrome have hypergastrinemia, the majority have hyperplasia of enterochromaffin-like cells, and about 3 percent have carcinoid tumors.156 , 157 However, more than 90 percent of the carcinoid tumors have occurred in patients with multiple endocrine neoplasia type 1 a subgroup that includes only about 25 percent of all patients with the ZollingerEllison syndrome. These data suggest that factors other than gastrin may be important in the genesis of gastric carcinoid tumors in patients with the ZollingerEllison syndrome.156 In humans the increase in plasma gastrin concentrations in response to the inhibition of gastric acid secretion is not as marked as it is in rats.158 Even so, omeprazole causes a 2-fold to 4-fold increase in fasting and postprandial plasma gastrin concentrations, and occasionally a 10-fold increase20 , 21 , 52 , 56 , 71 , 149 150 151 152 153 154 155 156 157 158 159 160 161 162; plasma gastrin concentrations return to normal two to four weeks after the discontinuation of omeprazole.20 , 160 Some studies have examined 24-hour profiles of plasma gastrin concentrations.23 , 160 , 161 The increase in 24-hour gastrin profiles in patients given 20 mg of omeprazole a day is much more than that in patients given 150 mg of ranitidine twice a day23 , 160 but comparable to that in patients who have had a parietal-cell vagotomy161 and much lower than the increase that may occur in patients with pernicious anemia.163 The limited data on long-term treatment with omeprazole (20 to 60 mg per day) in patients with normal levels of gastrin secretion before treatment79 , 162 , 164 indicate that such treatment results initially in fasting hypergastrinemia (the increase in plasma gastrin levels is typically 3-fold but occasionally as high as 10-fold). The plasma gastrin levels may stabilize after three months165 or continue to rise162; for example, in one study 25 percent of the patients had plasma gastrin concentrations of more than 500 pmol per liter after one year of therapy.79 , 162 , 164 , 165 The effect of both short-term and long-term treatment with omeprazole (20 to 40 mg per day for six weeks) on gastric oxyntic mucosal endocrine cells (which include the enterochromaffin-like cells) has been studied.121 , 122 , 157 , 158 , 164 165 166 167 168 169 Treatment with omeprazole for 6 weeks158 , 164 , 166 or 16 weeks167 had no effect on the number of endocrine cells. Some patients,164 but not others,165 with resistant acid-peptic disease treated with omeprazole for one to two years have had a slight but significant increase in the number of gastric mucosal endocrine cells. In patients with the ZollingerEllison syndrome who had hypergastrinemia and hyperplasia of enterochromaffin-like cells121 , 122 , 157 , 166 167 168 treatment with omeprazole (which does not change plasma concentrations of gastrin in these patients) for up to four years did not cause a further increase in the number of enterochromaffinlike cells.157 , 168 , 169 Overall, although short-term therapy with omeprazole apparently produces slight hypergastrinemia, it is safe. Long-term treatment may produce sufficient hypergastrinemia to cause hyperplasia of enterochromaffin-like cells and possibly carcinoid tumors in some patients. However, only long-term studies can establish the risk of such an occurrence and define the risk in relation to the benefit of treatment. For example, in an elderly patient with severe esophagitis, long-term treatment with omeprazole appears to be safe, but in a young

patient the possible risk of a gastric carcinoid tumor with such treatment might need to be balanced against the risk of other treatments. Other therapeutic options in young patients include antireflux surgery, intermittent omeprazole therapy (in low or full doses), continuous treatment with high doses of H2-receptor antagonists, and even continuous omeprazole therapy in combination with an antrectomy to abolish the hypergastrinemia. One possibility being explored now is treatment with omeprazole three days a week170 , 171; this approach appears to reduce the recurrence of duodenal ulcers,172 but not esophagitis.173 Because omeprazole, like H2-receptor antagonists, inhibits the secretion of gastric acid, its administration is associated with a reversible increase in bacterial-cell counts and nitrosamine levels in the stomach.174 Such changes could theoretically lead to an increased risk of both gastrointestinal infections175 and gastric cancer.176 It has been suggested that chronic hypergastrinemia may be a risk factor for carcinoma of the colon a suggestion that is apparently refuted by the absence of an increased incidence of colonic carcinoma in patients with pernicious anemia.177 , 178

Probable Role of Omeprazole in Acid-Peptic Diseases

Short-term omeprazole treatment is safe and effective. It heals duodenal and possibly gastric ulcers more rapidly than conventional doses of H2-receptor antagonists, and it can heal ulcers that are resistant to conventional or large doses of H2-receptor antagonists. More importantly, omeprazole is markedly superior to H2-receptor antagonists for the treatment of reflux esophagitis and is currently the best available drug for patients with the ZollingerEllison syndrome. In addition, although not yet generally available, intravenous omeprazole effectively reduces the secretion of gastric acid,179 , 180 and thus the drug may find a use in intensive care units.181 Nevertheless, in many circumstances the precise role of omeprazole remains to be clearly defined. Although omeprazole heals peptic ulcers more rapidly than H2-receptor antagonists, the latter drugs will heal more than 90 percent of such ulcers if given for a sufficient length of time. Omeprazole therapy thus offers no clear superiority for most patients with a duodenal or gastric ulcer. On the other hand, omeprazole is the only drug capable of relieving symptoms and healing the mucosa in some patients with reflux esophagitis. However, since the relapse rates after omeprazole therapy are similar to those for other agents, patients with severe disease are likely to require long-term treatment with omeprazole. The limited long-term data available are reassuring, but continued surveillance of patients taking omeprazole will be required before the risks of long-term therapy, if any, can be quantified.

Source Information
From the Oklahoma Foundation for Digestive Research, 711 Stanton L. Young Blvd., Suite 501, Oklahoma City, of 73104, where reprint requests should be addressed to Dr. Maton.

Reference :

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Translate : Omeprazol adalah yang pertama dari kelas baru obat yang menghambat sekresi lambung dengan mengubah aktivitas H + / K +-ATPase, 1 2 3 langkah akhir yang umum dari sekresi asam, dalam sel parietal lambung. Penemuan omeprazol telah menyebabkan wawasan baru ke dalam mekanisme sekresi lambung, pengetahuan tentang asal-usul tumor pencernaan tertentu, dan pengembangan pengobatan baru untuk penyakit asam lambung-. Di Amerika Serikat, omeprazol telah disetujui hanya untuk penggunaan jangka pendek pada pasien tertentu dengan esofagitis refluks dan untuk pasien dengan sindrom Zollinger-Ellison, karena kekhawatiran yang diangkat oleh hasil studi jangka panjang dari toksisitas pada hewan, tetapi dalam banyak negara penggunaan yang disetujui jauh lebih luas. Ulasan ini akan membahas fitur farmakologis dari omeprazole dan hasil uji coba dari obat pada pasien dengan ulkus duodenum, ulkus lambung, refluks esofagitis, dan sindrom Zollinger-Ellison.

Ilmu farmasi Asam Lambung Sekresi, H + / K +-ATPase, dan Aksi Omeprazol Sekresi asam klorida oleh sel parietal lambung akhirnya tergantung pada fungsi dari proton, (ion hidrogen) pump.1 2 pompa ini adalah H + / K +-ATPase, enzim membran-spanning yang menggunakan energi yang dilepaskan oleh metabolisme ATP untuk memindahkan proton (sebenarnya, ion hidronium) melintasi membran dalam pertukaran untuk kalium ions4, 5 (Gambar 1 Skema 1Figure Diagram Aksi Omeprazol pada your parietal lambung.). H + / K +ATPase terdiri dari dua subunit yaitu 111.000 dalton- subunit, yang mengkatalisis hidrolisis ATP dan transport ion, dan subunit yang lebih kecil, yang fungsinya tidak diketahui. Dalam keadaan nonsecreting, H + / K +-ATPase terletak di vesikula dalam sitoplasma sel. Karena vesikel mengandung potasium dan tidak ada membran vesikuler yang kedap ion kalium, pompa inactive.4, 5 Pada aktivasi sel parietal oleh stimulus yang tepat, seperti histamin, H + / K +ATPase translocates ke membran plasma yang canaliculus sekresi dari, parietal cell.6 7 Aspek ekstraselular H + / K - ATPase demikian terkena ion kalium, dan karena ada peningkatan terkait dalam permeabilitas membran untuk kalium, 5 sel mampu mensekresikan asam pada pH sekitar 1,0. Omeprazol telah ditunjukkan dalam beberapa spesies untuk menghambat sekresi asam dengan menghambat H + / K +-ATPase.8 9 10 Omeprazol adalah basis, lipofilik lemah dengan pK dari 4,0. Hal ini diserap dalam usus dan mencapai sel-sel parietal pada lambung melalui aliran darah. Pada pH sekitar 7 omeprazol tidak dikenakan biaya dan dapat menyeberangi membran sel (Gambar 1). Namun, dalam canaliculus yang keluar dari sel aktif mensekresi parietal lambung, dimana obat ini terkena pH kurang dari 2,0, omeprazol menjadi terprotonasi. Karena itu berhenti menjadi lipofilik dan terjebak dan terkonsentrasi. Omeprazol sendiri tidak aktif, tetapi di bawah kondisi asam waktunya akan diubah ke bentuk aktif, sulfenamide11, 12 yang bereaksi secara kovalen dengan kelompok sulfhidril dari residu sistein pada permukaan ekstraselular dari subunit H + / K +-ATPase dan menghambat aktivitas enzim (Gbr. 1). Dimulainya kembali sekresi asam setelah pemberian omeprazol hampir pasti membutuhkan sintesis baru H + / K +-ATPase protein.13 The paruh H + / K +-ATPase adalah sekitar 18 jam.

Farmakokinetik dan farmakodinamik Paparan asam lambung menurunkan omeprazole dan mengarah ke mulut yang buruk bioavailability.14 Obat Oleh karena itu telah dirumuskan dalam pH-sensitif butiran yang melepaskan omeprazole hanya ketika pH di atas 6. Dengan formulasi ini bioavailabilitas omeprazol adalah konsentrasi puncak sekitar 50 percent.14 plasma terjadi dua sampai empat jam setelah administration15 oral dan cenderung meningkat selama beberapa hari pertama pengobatan, mungkin karena penghambatan peningkatan hasil sekresi asam lambung dalam degradasi kurang omeprazol dalam lumen lambung. The plasma paruh omeprazol adalah sekitar 60 menit, 16 tetapi karena ini terkait kovalen untuk H + / K +-ATPase, durasi tindakan dari dosis tunggal melebihi 24 hours.17 Tingkat

penghambatan sekresi asam sehingga tidak berkorelasi dengan konsentrasi plasma obat, tetapi tidak berkorelasi dengan daerah di bawah konsentrasi plasma-waktu curve.18 A dosis 20 mg-tunggal omeprazol menghambat sekresi asam dengan 65 persen setelah 4 sampai 6 jam dan sebesar 25 persen setelah 24 jam , 18 namun dengan peningkatan inhibisi dosis berikutnya, mencapai dataran tinggi setelah empat doses.18 ini peningkatan aktivitas ini karena baik untuk bioavailabilitas meningkat dan penghambatan H + lebih / K +-ATPase molekul. Penghambatan kondisi-mapan sekresi asam selama pengobatan dengan 20 mg omeprazol per hari bervariasi dari orang ke orang: berkisar 35 sampai 65 persen, berdasarkan pengukuran sekresi asam 24 jam setelah pemberian obat, 18 19 20 dan 30 sampai 100 persen, berdasarkan pengukuran dari 24 jam keasaman lambung ditentukan oleh pH intragastrik, 21, 22 telah dilaporkan. Memang, dalam beberapa mata pelajaran 150 mg ranitidine dua kali sehari menghambat keasaman lambung lebih efektif selama periode 24-jam dari 20 mg omeprazole sehari. Dengan dosis yang lebih besar dari omeprazole, variasi antara pasien berkurang dan sekresi asam dihambat lebih profoundly.18, 21 Ketika pengobatan dihentikan, dibutuhkan setidaknya tiga hari untuk sekresi asam untuk kembali ke pretreatment levels.18, 21 hipersekresi Rebound tidak terjadi. 21, 23