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

beta-adrenergic receptor blocking agents (beta-blocking agents) have been widely used clinically for the treatment of various cardiovascular conditions. However, beta-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 beta 2 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 beta 1, beta 2, or 5-HT receptor occupancies for four beta-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 beta 1 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 beta 2 or central 5-HT receptor occupancies and the number of dreams. These findings suggest that beta 2 and/or 5-HT receptor occupancy is superior to beta 1 receptor occupancy as an index for the sleep disorders.