DOSING RATE-DEPENDENT RELATIONSHIP BETWEEN PROPRANOLOL PLASMA-CONCENTRATION AND BETA-BLOCKADE

The effect of propranolol dosing rate on beta-blockade was studied in human volunteers after administration of a conventional tablet and a sustained release capsule. The slope of the plot of the percentage of reduction in the heart rate against log plasma propranolol concentration was significantly greater after administration of a sustained release capsule than after administration of a conventional tablet. A marked leftward shift of the plasma concentration-response curve was also observed in rabbits as the infusion rate was decreased over the same infusion period. This shift was not altered by pretreatment with 6-hydroxydopamine and plasma catecholamine levels were not affected by the rate of infusion, indicating that the contribution of sympathetic activation to the effect was minimal. By contrast to the anticlockwise hysteresis of the temporal response after propranolol, no such hysteresis was found with the more hydrophilic beta-adrenoceptor antagonist atenolol, or was there any leftward shift in the plasma concentration- response relationship. Data from the isolated guinea pig atrial preparation also showed anticlockwise hysteresis and a leftward shift of the concentration-response curve at a low propranolol input rate, whereas no shift was observed with more hydrophilic beta-blockers such as atenolol, pindolol and metoprolol. An initial response was observed after 5 to 10 min of treatment but continued exposure to a constant concentration of propranolol over 40 min resulted in a further increase in effect. The decrease in heart rate induced by propranolol was observed in the presence of a large dose of the hydrophilic beta-blocker, CGP-12177 [(+/-)-4-(3-t-butylamino-2-hydroxypropoxy)-benzimidazole-2-one hydrochloride], but no heart responses were observed with the hydrophilic agonist, isoproterenol, and the hydrophilic antagonist, atenolol, under the same conditions. These data suggest that the dosing rate-dependent concentration-response relationship is due to the presence of two distinct beta-adrenoceptor binding sites on the surface membrane which differ in lipophilic characteristics. Only lipophilic drugs would be accessible to the more lipophilic site which is responsible for a delayed response.