Professional Documents
Culture Documents
Omeprazole
Omeprazole
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
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.
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.
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.
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<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 six-month relapse rates were similar (41 to 72 percent) for omeprazole and H2receptor 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
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 4
Differences 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).
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.
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