Loss of acid suppression during dosing with H₂‐receptor antagonists

SUMMARY

The suppression of intragastric acidity with H₂‐receptor antagonists may diminish with repeated administration. To assess the degree and dose‐dependance of this tolerance after short‐term dosing, two doses of the H₂‐receptor antagonists, ranitidine (300 mg node or q.d.s.) and sufotidine (300 mg or 600 mg b.d.), were given to healthy volunteers for 1 and 2 weeks, respectively. After 1 and 7 days of dosing with ranitidine 300 mg q.d.s. the median 24‐h and night‐time pH, measured by continuous 24‐h pH‐metry, dropped from 3.7 to 2.2 and 5.8 to 3.2, respectively (P < 0.0001 for both). The decline in median pH with ranitidine 300 mg node was only significant during the night (from 4.1 to 2.9) (P < 0.04). There was little change in plasma gastrin concentrations between days 1 and 7 with either dosage. With sufotidine 300 mg b.d. and 600 mg b.d. for 1 and 14 days, the median 24‐h pH fell from 3.7 to 2.1 and from 4.6 to 2.6, respectively (P < 0.0001). The equivalent medians for the night decreased‐from 6.3 to 2.3 and from 6.6 to 3.1 (P < 0.0001). Gastrin concentrations did not change after 14 days of dosing with sufotidine 300 mg b.d., but increased significantly during dosing with sufotidine 600 mg b.d. (P < 0.001).

Significant tolerance developed in 7‐14 days and it seemed to show some dose relationship. The mechanisms behind tolerance and the role of gastrin are discussed, but remain unclear.