Loperamide, an Opiate Analog, Differently Modifies the Adrenocorticotropin Responses to Corticotropin-Releasing Hormone and Lysine Vasopressin in Patients with Addison’s Disease

Abstract

Loperamide is a peripheral opiate agonist able to inhibit ACTH secretion. In this work, the interactions between loperamide and two ACTH secretagogues, lysine vasopressin (LVP) and corticotropin-releasing hormone (CRH), were investigated in patients with Addison’s disease. After loperamide (16 mg orally) or placebo administration, 5 patients received LVP (0.06 IU/kg i.v. over 1 h) and 6 patients received oCRH (1 µg/kg i.v. as bolus). In all patients loperamide induced a significant fall in plasma ACTH levels. LVP increased ACTH levels after both loperamide (from 48 ± 17.3 to a peak of 95 + 21 pmol/l) and placebo (from 231 ± 59.5 to 365 ± 86.6 pmol/l): the interaction between treatments and time was not significant. CRH caused a rise in plasma ACTH after both loperamide (from 30 ± 16.6 to a peak of 108 ± 31 pmol/l) and placebo (from 98.5 ± 47 to 211 ± 61.7 pmol/l): the interaction between treatments and time was significant, and the first phase of CRH-induced ACTH secretion was significantly lower after loperamide. These data demonstrate that loperamide differently modifies the stimulatory action of LVP and CRH on ACTH secretion: namely, LVP and loperamide act in an additive manner, while CRH and loperamide interact in a non additive way. Although these findings might be explained by the involvement of different intracellular ACTH-secreting mechanisms, an influence of loperamide on some suprapituitary factors modulating the ACTH response is suggested.

Loperamide Inhibits Corticotrophic Cell Function by a Naloxone-lnsensitive Mechanism in the Rat in vitro

“…Merritt et al [3] have reported about a suppressive effect of loperamide on a calmodulin-dependent phosphodiesterase which was significant between 10"6 and 10"4 M. Both modes of action have been shown to exist in the gastrointesitnal system. While the antidiar rheal activity of loperamide can be inhibited by naloxone [4], loperamide's antisecretoiy action in the colon is caused by a block of the calmodulin system [5], Recently, loperamide was reported to suppress ACTH and cortisol levels in normal subjects and in patients with Addison's disease [6][7][8]. Loperamide also modified the adrenocorticotropin responses to corticotropin-releasing hormone (CRH) and to lysine vasopressin [7,8].…”

“…While the antidiar rheal activity of loperamide can be inhibited by naloxone [4], loperamide's antisecretoiy action in the colon is caused by a block of the calmodulin system [5], Recently, loperamide was reported to suppress ACTH and cortisol levels in normal subjects and in patients with Addison's disease [6][7][8]. Loperamide also modified the adrenocorticotropin responses to corticotropin-releasing hormone (CRH) and to lysine vasopressin [7,8]. The sup pressive effect of loperamide on ACTH secretion was shown to be reversed by naloxone [6].…”