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 s ustained release capsule. The slope of the plot of the percentage of r eduction in the heart rate against log plasma propranolol concentratio n was significantly greater after administration of a sustained releas e capsule than after administration of a conventional tablet. A marked leftward shift of the plasma concentration-response curve was also ob served in rabbits as the infusion rate was decreased over the same inf usion period. This shift was not altered by pretreatment with 6-hydrox ydopamine and plasma catecholamine levels were not affected by the rat e of infusion, indicating that the contribution of sympathetic activat ion to the effect was minimal. By contrast to the anticlockwise hyster esis of the temporal response after propranolol, no such hysteresis wa s found with the more hydrophilic beta-adrenoceptor antagonist atenolo l, or was there any leftward shift in the plasma concentration- respon se relationship. Data from the isolated guinea pig atrial preparation also showed anticlockwise hysteresis and a leftward shift of the conce ntration-response curve at a low propranolol input rate, whereas no sh ift 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 t- butylamino-2-hydroxypropoxy)-benzimidazole-2-one hydrochloride], but n o heart responses were observed with the hydrophilic agonist, isoprote renol, and the hydrophilic antagonist, atenolol, under the same condit ions. These data suggest that the dosing rate-dependent concentration- response relationship is due to the presence of two distinct beta-adre noceptor binding sites on the surface membrane which differ in lipophi lic characteristics. Only lipophilic drugs would be accessible to the more lipophilic site which is responsible for a delayed response.