Duration and selectivity in beta-adrenoceptor blocking action of a beta-adrenoceptor blocking drug, D-32 in conscious...

In conscious dogs, the selectivity and duration of beta-blocking activity, and serum concentration of a beta-blocking agent, D-32 [dl-1-tert-butylamino-3-(2,3-dimethylphenoxy)-2-propanol hydrochloride] was compared to that of propranolol, pindolol, atenolol and IPS-339 [dl-1-tert-butylamino-3-(-9-fluorenylideneaminoxy)-2-propanol hydrochloride]. Ratios of doses causing a 50% inhibition of tachycardia to that on hypotension induced by isoprenaline were as follows: D-32 (0.69), propranolol (0.67), atenolol (0.03) and IPS-339 (6.3). Thus, present experiments indicate that, unlike atenolol and IPS-339, D-32, propranolol and pindolol are non-selective beta-adrenoceptor blocking agents. Atenolol and IPS-339, however, selectively blocked cardiac beta1, receptors and vascular beta2-receptors respectively, as would be expected. In an optimal dose range these two drugs can be used satisfactorily as a pharmacological tool for inhibiting responses mediated via the respective beta-receptors. After oral administration, the pharmacological half-life (time required for 50% recovery of beta-blocking action) was 15.8 +/- 4.5 h for propranolol (3 mg/kg), 21.8 +/- 6.4 h for D-32 (0.5 mg/kg), 30.5 +/- 3.1 h for atenolol (6 mg/kg) and 30-35 h for pindolol (0.2 mg/kg). The pharmacological half-life after i.v. administration was 4.4 +/- 0.7 h for propranolol (300 microgram/kg) and 5.9 +/- 0.4 h for D-32 (150 microgram/kg), whereas the serum half-like (time required for 50% decrease in serum concentration) of propranolol was 1.4 h and that of D-32 was 1.3 h. The values for pharmacological half-life and serum half-life were significantly different. Thus, for determination of administration frequency and dosage of beta-adrenoceptor blocking drugs, not only pharmacokinetic but also pharmacological data (duration of action) are essential.