Omeprazole

Abstract

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 2- 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. 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 (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 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. 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.