Prediction of sleep disorders induced by β-adrenergic receptor blocking agents based on receptor occupancy

  • Yasuhiko Yamada
  • Fuminori Shibuya
  • Jun Hamada
  • Yasufumi Sawada
  • Tatsuji Iga


β-adrenergic receptor blocking agents (β-blocking agents) have been widely used clinically for the treatment of various cardiovascular conditions. However, β-blocking agents are liable to cause sleep disturbance, such as vivid dreams, nightmares, increased waking, and insomnia. The mechanisms of the sleep disorders are not known, but several may conceivably be responsible for these CNS-related side effects. In the present study, we hypothesized that the sleep disorders are induced by the blockade of central or peripheral β2 receptors and/or central serotonin (5-HT) receptors. To verify the hypothesis, we retrospectively analyzed the relationships between the extent of the sleep disorders and the β1, β2, or 5-HT receptor occupancies for four β-blocking agents (atenolol, metoprolol, pindolol, and propranolol). No significant correlations were observed among pharmacokinetic/physicochemical parameters (therapeutic dose, plasma concentration, plasma unbound concentration, cerebrospinal fluid concentration, and lipid solubility) and pharmacodynamic parameters (the scores of the sleep disorders such as the number of dreams). Furthermore, no significant relationship (correlation coefficient: r<0.3) was observed between β1 receptor occupancies of the drugs and the number of dreams. On the other hand, good relationships (r>0.95) were observed between central and peripheral β2 or central 5-HT receptor occupancies and the number of dreams. These findings suggest that β2 and/or 5-HT receptor occupancy is superior to β1 receptor occupancy as an index for the sleep disorders.

Key Words

β-blocking agents sleep disorder β1 receptor β2 receptor 5-HT receptor receptor occupancy 


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Copyright information

© Plenum Publishing Corporation 1995

Authors and Affiliations

  • Yasuhiko Yamada
    • 1
  • Fuminori Shibuya
    • 1
  • Jun Hamada
    • 1
  • Yasufumi Sawada
    • 1
  • Tatsuji Iga
    • 1
  1. 1.Department of Pharmacy, The University of Tokyo Hospital, Faculty of MedicineThe University of TokyoTokyoJapan

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