Tolerance to oral H2-receptor antagonists

Wilder‐Smith, Clive H.; Ernst, T.; Gennoni, M.; B, Zeyen; Halter, F; Merki, H. S.

doi:10.1007/bf01537246

Cited by 122 publications

(73 citation statements)

References 24 publications

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“…As already stated, although very effective in humans for treating peptic ulcers, long-term H2 antagonist treatment is complicated in some patients by the development of tolerance and recurrency (2,5,19,23,24,57). It is tempting to speculate that the inverse agonism displayed by the tested H2 antagonists, consequently resulting in an upregulation of H2 receptors, contributes to the development of tolerance after chronic treatment (2,5,19,23,24).…”

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confidence: 96%

“…In vivo modulation of H2 receptor function after treatment of H2 antagonists has been reported (2,(19)(20)(21)(22). Prolonged H2 receptor blockade was found to result in increased parietal cell sensitivity to H2 agonists (22), increased intragastric hyperacidity after abrupt withdrawal (21), and the development of tolerance (2,5,19,23,24). Coruzzi and Bertaccini (22) and Nwokolo et al (21) hypothesized that these observations could be explained by an upregulation of H2 receptors.…”

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confidence: 96%

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Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors.

Smit

Leurs

Alewijnse

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

213

148

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Histamine H2 receptors transfected in Chinese hamster ovary (CHO) cells are time-and dosedependently upregulated upon exposure to the H2 antagonists cimetidine and ranitidine. This effect appears to be H2 receptor-mediated as no change in receptor density was observed after H1 or H3 antagonist treatment or after incubation with the structural analogue of cimetidine, VUF 8299, which has no H2 antagonistic effects. By using transfected CHO cells expressing different densities of wild-type H2 receptors or an uncoupled H2Leut24Ala receptor, the histamine H2 receptor was found to display considerable agonist-independent H2 receptor activity. Cimetidine and ranitidine, which both induce H2 receptor upregulation, actually functioned as inverse agonists in those cell lines displaying spontaneous agonistindependent H2 receptor activity. Burimamide, on the other hand, was shown to act as a neutral antagonist and did as expected not induce H2 receptor upregulation after long-term exposure. The displayed inverse agonism of H2 antagonists appears to be a mechanistic basis for the observed H2 antagonist-induced H2 receptor upregulation in transfected CHO cells. These observations shed new light on the pharmacological classification of the H2 antagonists and may offer a plausible explanation for the observed development of tolerance after prolonged clinical use.Following the discovery of burimamide as a selective histamine H2 receptor antagonist (1) various related drugs (cimetidine, ranitidine, famotidine, nizatidine) have proven to be of great importance in the regulation of gastric acid secretion (2). The actual target of these drugs have recently been questioned (3, 4), but is generally considered to be the H2 receptor on the gastric parietal cell (4). As such, the H2 antagonists constitute currently one of the prominent therapies for duodenal and gastric ulcers (5). These drugs have been widely prescribed and are currently also clinically evaluated as immunosuppressants (6) and for the treatment of central nervous system disorders (7-10).The histamine H2 receptor is a member of the large multigene family of G-protein coupled receptors (GPCR) (11). Functionality and expression of members of the GPCR family are generally dynamically regulated after agonist or antagonist exposure (12,13 Studies examining the molecular mechanism underlying H2 receptor function have been greatly facilitated by the cloning of the genes encoding the histamine H2 receptor (25-28). Model systems, expressing a homogeneous population of (mutant) H2 receptors, are currently available for studies regarding H2 receptor function and regulation (18,29,30). In the present study we describe upregulation of H2 receptors after prolonged treatment of transfected Chinese hamster ovary (CHO) cells with some H2 antagonists. In our study, we observed that the histamine H2 receptor shows a spontaneous, histamine-independent activity. For some GPCRs, increased basal agonist-independent receptor activity can be inhibited by certain antagonists referred to as...

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confidence: 96%

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confidence: 96%

Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors.

Smit

Leurs

Alewijnse

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

213

148

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“…For example, the selective affinity of the inverse agonists cimetidine and metiamide for histamine H2 receptors has been linked to tolerance to H2 receptor blockade (Nwolko et al, 1990;Wilder-Smith et al, 1990;Deakin and Williams, 1992). This tolerance is believed to occur through the elevation of histamine receptor levels (Nwolko et al, 1991).…”

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confidence: 99%

Efficacy as a Vector: the Relative Prevalence and Paucity of Inverse Agonism

Kenakin¹

2004

Mol Pharmacol

201

149

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This article describes the expected phenotypic behavior of all types of ligands in constitutively active receptor systems and, in particular, the molecular mechanisms of inverse agonism. The possible physiological relevance of inverse agonism also is discussed. Competitive antagonists with the molecular property of negative efficacy demonstrate inverse agonism in constitutively active receptor systems. This is a phenotypic behavior that can only be observed in the appropriate assay; a lack of observed inverse agonism is evidence that the ligand does not possess negative efficacy only if it can be shown that constitutive receptor activity is present. In the absence of constitutive activity, inverse agonists behave as simple competitive antagonists. A survey of 105 articles on the activity of 380 antagonists on 73 biological G-protein-coupled receptor targets indicates that, in this sample dataset, 322 are inverse agonists and 58 (15%) are neutral antagonists. The predominance of inverse agonism agrees with theoretical predictions which indicate that neutral antagonists are the minority species in pharmacological space.

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“…5±7 Our study clearly showed that the marked inhibition of gastric acidity observed at day 7 with omeprazole 20 mg and 40 mg remained stable over 3 months. These data con®rmed the absence of tolerance to proton pump inhibitors contrary to H 2 -blockers 10 and the absence of a progressive increase in acid suppression despite prolonged inhibition of the proton pump. Moreover, 24-h pH pro®les remained unchanged between day 7 and day 90.…”

Section: Discussionmentioning

confidence: 64%

Twenty‐four‐hour intragastric acidity and plasma gastrin during 3‐month treatment with omeprazole in healthy subjects

Delchier

Bénamouzig

Stănescu

et al. 1997

Aliment Pharmacol Ther

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Background: Prolonged treatment with omeprazole 20 or 40 mg/day is sometimes required, especially for severe oesophagitis. However, information about long‐term effects on intragastric acidity and plasma gastrin response with such drug regimens is scarce. Methods: Sixteen healthy subjects (11 men, 5 women, mean age 29 years) randomly received either 20 or 40 mg of omeprazole once daily (at 08.00 h) for 3 months. Gastric pH was recorded every 6 s for 24 h from noon to noon under standardized conditions, and blood samples were collected hourly in order to determine the 24‐h plasma gastrin response on day 0 (pre‐entry), day 7, day 28 and day 90. Results: From day 0 to day 7, 24‐h median pH increased from 1.7 to 4.6 and mean percentage of time at pH < 4 decreased from 89% to 35% with omeprazole 20 mg. Respective values with omeprazole 40 mg were 1.9 to 4.3, and 89% to 34%. Inhibition of gastric acidity remained unchanged during the 3 months of treatment. Despite similar effects on the basis of 24‐h analysis, the decrease in daytime acidity was slightly higher with omeprazole 40 mg than with omeprazole 20 mg. Twenty‐four‐hour integrated plasma gastrin significantly increased with both drug regimens between day 0 and day 7 (P < 0.01), and between day 7 and day 28 (P < 0.01) with omeprazole 40 mg; there was no significant increase between day 28 and day 90 with either of the drug regimens. Conclusion: Omeprazole 20 and 40 mg/day provides long‐term stable acid suppression with a progressive increase in gastrin response, stabilizing after 2 months of treatment.

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Tolerance to oral H2-receptor antagonists

Cited by 122 publications

References 24 publications

Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors.

Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors.

Efficacy as a Vector: the Relative Prevalence and Paucity of Inverse Agonism

Twenty‐four‐hour intragastric acidity and plasma gastrin during 3‐month treatment with omeprazole in healthy subjects

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