Effect of route of administration on the relationship between β‐adrenergic blockade and plasma propranolol level

The antagonism of isoproterenol‐induced tachycardia by orally and intravenously administered propranolol was measured in 5 subjects and related to the plasma propranolol concentration. Two hours after oral administration of a single dose of propranolol, the degree of beta blockade associated with a given plasma propranolol concentration was greater than that seen with the same concentration achieved by intravenous administration. After 6 hours, this disparity was no longer apparent. During long‐term 6 hour administration, the effect of the twenty‐first dose both 2 and 6 hours after administration was the same as that resulting from similar plasma levels achieved by intravenous administration. These findings can be explained by the formation after single oral doses of an active metabolite, 4‐hydroxypropranolol, which has a shorter half‐life than does the parent drug. This metabolite is not produced during intravenous administration of single doses. However, at the end of a 6 hour dosage interval and after chronic oral administration, the effects of propranolol could be attributed entirely to circulating levels of the parent drug.