Pharmacodynamics of Racemic and S(—)‐Atenolol in Humans

The cardiovascular actions of racemic atenolol (RSATN) have been well characterized in humans, but the actions of S(—)‐atenolol (SATN) when administered alone are unknown. In this study, responses of heart rate (HR) and Doppler‐derived aortic blood flow profiles to upright treadmill exercise were compared after oral administration of 50 mg SATN and 100 mg RSATN in eight healthy, adult, male volunteers. After a single‐blind, placebo run‐in period, subjects were randomly allocated in a double‐blind, crossover fashion to receive SATN and RSATN. Each study period was separated by a 7‐day washout period. Multiple submaximal exercise tests were performed and data were collected over the 24 hours after each treatment. Both SATN and RSATN significantly (P < .05) blunted peak exercise HR by 38 ± 3 and 37 ± 3 beats/mint, respectively. Aortic blood flow acceleration measured during peak exercise decreased after SATN and RSATN, by 13 ± 4 and 13 ± 3 m/sec², respectively (P < .05). No difference in hemodynamic effect was observed between treatments. Pharmacodynamic parameters derived from plasma S(—)‐atenolol concentration‐effect (HR) curves after SATN, RSATN, and total atenolol plasma concentrations after RSATN did not differ significantly. Predicted maximum reductions in heart rate (E_max) and EC₅₀ for S(—)‐atenolol after SATN were 39.6 ± 5.8 beats/min and 38.4 ± 40.9 ng/ml versus 34.5 ± 8 beats/min and 25.9 ± 29.9 ng/ml for RSATN, respectively. The E_max and EC₅₀ for total atenolol plasma concentrations after RSATN were 35.1 ± 8.4 beats/min and 50.2 ± 68 ng/ml, respectively. These data indicate that, after a single dose: (1) the negative chronotropic and inotropic activities of 100 mg oral RSATN reside in the S(—)‐enantiomer and R(+)‐atenolol exerts no detectable cardiovascular activity, and (2) pharmacodynamic modeling of the total plasma concentration accurately describes the HR effect of the active enantiomer. 1994 American College of Clinical Pharmacology