Loperamide: blockade of calcium channels as a mechanism for antidiarrheal effects.

The antidiarrheal opiates loperamide, fluperamide, diphenoxylate and fetoxylate inhibited binding of [3H]nitrendipine to membranes from guinea-pig cerebral cortex with Ki values of 0.5 to 10 microM. Loperamide and fluperamide reversed the tiapamil elicited lowering of [3H]nitrendipine binding with IC50 values of 0.2 to 0.5 microM, indicating a verapamil-like action of these drugs. An oral dose of 1 mg/kg of loperamide reduced gastrointestinal motility and gave concentrations of 0.45 +/- 0.19, 0.38 +/- 0.22 and 0.49 +/- 0.25 microM in the duodenum, jejunum and ileum, respectively. The apparent Ki for loperamide in preventing calcium-induced contractions of guinea-pig ileum depolarized with 80 mM potassium was 0.10 microM. We propose that calcium channel antagonism is responsible at least in part for the antidiarrheal actions of loperamide and related agents. Evidence includes the calcium antagonist actions of loperamide at antidiarrheal doses, the constipating effects of certain calcium antagonists and the failure of opiate antagonists to prevent some intestinal effects of loperamide.