OMEPRAZOLE is the First of a New Class of Drugs That Inhibit Gastric Secretion by Altering the...

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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 Zollinger—Ellison 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 Zollinger—Ellison 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. 1 Figure 1 Schematic Diagram of the Action of Omeprazole on a Gastric Parietal Cell.). H + /K + —ATPase consists of two subunits: the 111,000-dalton α subunit, which catalyzes the hydrolysis of ATP and transports ions, and the smaller β 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,

Transcript of OMEPRAZOLE is the First of a New Class of Drugs That Inhibit Gastric Secretion by Altering the...

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.PharmacologyGastric Acid Secretion, H+/K+ATPase, and the Action of OmeprazoleThe 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 1Schematic 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 PharmacodynamicsExposure 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 MetabolismTwo 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 OmeprazoleOmeprazole 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 gastrin-immunostaining 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 DiseasesDuodenal UlcerSeveral 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 2Differences 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 H2-receptor 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