Omeprazole

An Updated Review of its Pharmacology and Therapeutic Use in Acid-Related Disorders

Summary

Synopsis

Omeprazole is the first of a new class of drugs, the acid pump inhibitors, which control gastric acid secretion at the final stage of the acid secretory pathway and thus reduce basal and stimulated acid secretion irrespective of the stimulus.

In patients with duodenal or gastric ulcers, omeprazole as a single 20mg daily dose provides more rapid and complete healing compared with ranitidine 150mg twice daily or 300mg at nighttime, or cimetidine 800 or 1000 mg/day.

Patients poorly responsive to treatment with histamine H2- receptor antagonists respond well to omeprazole —most ulcers healed within 4 to 8 weeks of omeprazole 40 mg/day therapy. Omeprazole 20 or 40 mg/day has been administered as maintenance therapy for peptic ulcer disease for up to 5.5 years with very few ulcer recurrences.

In patients with erosive or ulcerative oesophagitis, omeprazole 20 or 40 mg/day produces healing in about 80% of patients after 4 weeks, and is superior to ranitidine with respect to both healing and symptom relief. Healing rates of >80% are achieved after 8 weeks in patients with severe reflux oesophagitis unresponsive to H2- receptor antagonists. Maintenance therapy with a daily 20mg dose prevents relapse in about 80% of patients over a 12- month period.

Omeprazole is considered to be the best pharmacological option for controlling gastric acid secretion in patients with Zollinger-Ellison syndrome. Daily dosages of 20 to 360 (median 60 to 70mg successfully reduce basal acid output to target levels (> 10 mmol/h or <5 mmol/h in patients with severe oesophagitis or partial gastrectomy) during treatment for up to 4 years.

Omeprazole is well tolerated in short term studies (up to 12 weeks); the reported incidence of serious side effects (about 1%) being similar to that seen in patients treated with an histamine H2- receptor antagonist. The longer term tolerability of omeprazole has been investigated in patients treated for up to 5.5 years. Slight hyperplasia, but no evidence of enter ochromaffin-like (ECL) cell dysplasia or neoplasia or ECL cell carcinoids has been reported. ECL cell carcinoids have been observed in rats after life-long treatment with high doses of omeprazole or ranitidine, or in rats with partial corpectomy; the weight of experimental evidence indicates that this is a result of prolonged hypergastrinaemia.

Thus, omeprazole is a highly effective alternative to other treatments available for reflux oesophagitis, and duodenal and gastric ulcers —including those conditions poorly responsive to histamine H2-receptor antagonists. The potential of omeprazole as prophylaxis for peptic ulcer and reflux oesophagitis is promising and awaits further confirmation of its long term safety. Nevertheless, omeprazole has now reached a stage of its development where it should receive careful consideration by prescribing clinicians as a first-line agent.

Pharmacological Properties

Omeprazole controls acid secretion by inhibition of gastric H+,K+-ATPase (the acid pump), the enzyme responsible for the final step in the secretion of hydrochloric acid by the gastric parietal cell. As a weak base, omeprazole concentrates in the acidic milieu of the secretory canaliculi where it is converted by acid to its active sulphenamide derivative. In this form the drug does not cross cell membranes and is trapped at its site of action. Thus, omeprazole provides an effective and specific means of controlling acid secretion regardless of the nature of the secretory stimulus, and inhibits both basal and stimulated gastric acid secretion.

Gastrin release from antral G cells is stimulated when gastric acid secretion is suppressed, therefore, like other acid inhibitors, omeprazole would be expected to increase plasma gastrin levels. Indeed, short term (<12 weeks) omeprazole treatment typically increases plasma gastrin levels by 2- to 4-fold — 24-hour levels after a 20mg daily dose are considerably less than those seen in patients with pernicious anaemia, comparable to those achieved with parietal-cell vagotomy, and slightly higher than those seen with ranitidine 150mg twice daily. During longer term therapy, omeprazole 20 or 40 mg/day initially increases plasma gastrin levels, with no further increase noted during extended therapy in most patients.

Studies have shown that the alterations in gastric mucosal morphology observed in rats administered very high doses of omeprazole for prolonged periods represent the effects of hypergastrinaemia occurring in response to profound inhibition of acid secretion. Proliferation of ECL cells in the oxyntic mucosa and the development of ECL-cell carcinoids has also been observed in rats with other antisecretory agents (including ranitidine) and following partial corpectomy. The consensus view from published data is that the moderate elevation in plasma gastrin levels observed in clinical studies with therapeutic doses of omeprazole is unlikely to result in clinically significant alterations in gastric morphology (see Tolerability summary).

Placebo-controlled studies in healthy volunteers indicate that omeprazole 40mg daily or more for greater than 4 days significantly reduces aspirin- and naproxen-induced gastric mucosal injury, confirming earlier findings from animal studies.

The bioavailability of omeprazole, administered as enteric-coated granules to limit preabsorption acidic degradation, is about 65% in healthy volunteers.

Peak plasma concentrations and AUC values increase with repeated administration, suggesting that absorption increases and/or first-pass hepatic metabolism becomes saturated. Omeprazole distributes rapidly and widely to extra vascular sites (Vβ = 0.31 L/kg). Although the drug is rapidly eliminated from plasma (mean half-life 0.5 to 1 hour), its antisecretory effect persists for much longer since it is preferentially concentrated in parietal cells where it covalently binds to H+, K+-ATPase. Elimination is almost entirely by metabolism, followed by primarily urinary excretion. The major plasma metabolites are hydroxyomeprazole and omeprazole sulphone — neither appears to be pharmacologically active.

The disposition of omeprazole does not appear to be altered in patients with renal disease, or in those undergoing haemodialysis. Increased age and liver disease delay plasma clearance of the drug but this does not necessitate dosage adjustment in these patient groups.

Therapeutic Use

The original review of omeprazole in the Journal established the role of the drug in the short term treatment of duodenal ulcer, and for reducing gastric acid hypersecretion in patients with Zollinger-Ellison syndrome, and demonstrated its potential in gastric ulcer and reflux oesophagitis. In the interim many more clinical trials have been published.

Omeprazole 20 mg/day provides a more rapid response and superior healing rates in patients with duodenal ulcer, and faster relief of associated symptoms, than ranitidine 150mg twice daily or 300mg at night-time, or cimetidine 800 to 1000 mg/day. At these dosages, healing rates were 93% after 4 weeks compared to 83% in patients treated with ranitidine. In patients with gastric ulcer, omeprazole 20 to 40 mg/day was also more effective than ranitidine 150mg twice daily or cimetidine 800 to 1000 mg/day, achieving healing rates of 73 and 91% after 4 and 8 weeks, compared with 62 and 85%, respectively, with ranitidine therapy in a meta-analysis of clinical studies. Omeprazole is highly effective in healing duodenal and gastric ulcers poorly responsive to histamine H2-receptor antagonist treatment, with almost all patients showing complete healing within 4 to 8 weeks at a daily dose of 40mg.

Relapse of healed duodenal ulcers after treatment with omeprazole or H2-receptor antagonists is withdrawn is frequent, and therefore maintenance therapy may be required. Weekend therapy (20mg administered daily for 3 days/week) appears to provide similar protection against relapse to a 10mg daily dose; 6-month relapse rates ranged from 23 to 29% compared with >60% in placebo-treated patients. Omeprazole 20 or 40 mg/day administered continuously for up to 5.5 years in a small number of patients provided complete protection against ulcer relapse.

Omeprazole 20, 40 and 60 mg/day is superior to placebo, ranitidine 300 mg/day and cimetidine 1600 mg/day in healing erosive and ulcerative lesions, and relieving symptoms in patients with reflux oesophagitis. After 4 weeks, healing rates were 81 and 6% in patients treated with omeprazole 20 or 40 mg/day and placebo, respectively, and 75 and 23% of patients were free of heartburn after 4 weeks. Relapse in patients with reflux oesophagitis occurs earlier and more frequently than in patients with duodenal ulcer. Patients often require long term treatment to prevent relapse: cumulative remission rates after 12 months were 78 and 15% during continuous and weekend (3 days/week) omeprazole therapy (20mg daily), respectively. Corresponding rates for medium and high dose continuous histamine H2-receptor therapy were 38 and 33%, respectively.

In patients with Zollinger-Ellison syndrome a median omeprazole dosage of 60 to 70 mg/day reduces and maintains basal acid output at target levels (> 10 mmol/h or <5 mmol/h in patients with severe oesophagitis or partial gastrectomy), and also rapidly relieves acid-related symptoms such as heartburn, abdominal pain and diarrhoea during treatment of up to 4 years.

Tolerability

Omeprazole is well tolerated in short term (> 12 weeks) clinical trials. The incidence of adverse events reported in 19000 individuals treated in clinical studies did not differ between omeprazoleor placebo-treated patients, and in comparative studies, the incidence (≈1% of patients) and spectrum of serious side effects was similar to that associated with H2-receptor antagonist therapy. Gastrointestinal symptoms are most frequently reported by patients receiving omeprazole or H2-receptor antagonists. Less than 2% of patients have discontinued omeprazole treatment because of adverse events in clinical trials, and there was no relationship between omeprazole dosage and incidence of adverse effects.

During long term (up to 5.5 years) administration of omeprazole at therapeutic doses, no ECL cell dysplasia or neoplasia has been observed.

Dosage and Administration

A daily 20mg dose is recommended for the treatment of duodenal and gastric ulcer, and reflux oesophagitis, although 40 mg/day may be required1 in patients with conditions poorly responsive to histamine H2-receptor antagonist therapy. Recurrence of reflux oesophagitis has been successfully prevented with daily 20 or 40mg doses while a lOmg daily dose appears promising in patients with duodenal ulcer.

In patients with Zollinger-Ellison syndrome, omeprazole 60 mg/day is recommended initially with individual adjustment to maintain target gastric acid output.

Dosage adjustment is not necessary in elderly patients, or in patients with renal or hepatic impairment.

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Correspondence to Donna McTavish.

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Various sections of the manuscript reviewed by: G. Bianchi Porro, Gastrointestinal Unit, L. Sacco Hospital, Milan, Italy; K.D. Bardhan, Rotherham District General Hospital, Rotherham, England; C.M. Bate, Department of Gastro-Enterology, Royal Albert Edward Infirmary, Wigan, England; S. Dahlgren, Department of Surgery, University of Umeå, Umeå, Sweden; J. Dent, Gastroenterology Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia; A.S. Guerreiro, Hospital Pulido Valente, Lisbon, Portugal; C. W. Howden, Division of Digestive Diseases and Nutrition, University of South Carolina School of Medicine, Columbia, South Carolina, USA; J.B.M.J. Jansen, Department of Gastroenterology, University Hospital, Leiden, The Netherlands; R.T. Jensen, Cell Biology Section, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland, USA; J. Lind, Department of Surgery II, University of Göteborg, Göteborg, Sweden; I.N. Marks, Gastro-Intestinal Clinic, Groote Schuur Hospital, Cape Town, South Africa; P.N. Maton, Oklahoma Foundation for Digestive Research, Oklahoma City, Oklahoma, USA; D. W. Piper, Royal North Shore Hospital, St Leonards, New South Wales, Australia; R.E. Pounder, University Department of Medicine, Royal Free Hospital, London, England; J. Rademaker, Division of Gastroenterology, McMaster University, Hamilton, Ontario, Canada; N. Takeguchi, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Toyama, Japan.

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McTavish, D., Buckley, M.M.T. & Heel, R.C. Omeprazole. Drugs 42, 138–170 (1991). https://doi.org/10.2165/00003495-199142010-00008

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Keywords

  • Omeprazole
  • Duodenal Ulcer
  • Ranitidine
  • Gastric Ulcer
  • Gastric Acid Secretion