Comparison of beta-adrenoceptor selectivity of acebutolol and its metabolite diacetolol with metoprolol and propranolol in normal man

Summary 1. The beta-adrenergic selectivity of diacetolol, the major metabolite of acebutolol, has been compared with that of acebutolol, metoprolol and propranolol in 11 normal subjects.2. Bronchial and cardiac beta-adrenoceptor blockade were assessed on separate occasions after diacetolol 600 mg, acebutolol 400 mg, metoprolol 200 mg, propranolol 80 mg and placebo.3. Bronchial beta-adrenoceptor blockade was assessed as the displacement of the bronchodilator dose response curve to inhaled isoprenaline after each beta blocking drug compared to placebo and expressed as the dose ratio. Bronchodilatation was measured as change in specific airway conductance (sGaw) in the body plethysmograph. Cardiac beta-adrenoceptor blockade was assessed as the percentage reduction in exercise heart rate during the 5th minute of exercise at 70% of the subject's maximum work rate.4. There was a significant reduction in exercise heart rate with all 4 beta-blocking drugs when compared with placebo, 22% for diacetolol, 24% for acebutolol, 25% for propranolol and 28% for metoprolol. The reduction with metoprolol was significantly greater than the reduction with the other three beta-adrenoceptor antagonists.5. Mean dose ratios for the airway isoprenaline dose response curves after each of the 4 beta-blocking drugs were 2.4 for diacetolol, 2.7 for metoprolol, 8 for acebutolol and 72 for propranolol. The difference between diacetolol and metoprolol was not significant.6. Thus diacetolol appears to be more cardioselective than acebutolol and both are more cardioselective than propranolol in man. Metoprolol is probably more cardioselective than diacetolol though interpretation of the differences in exercise heart rate is complicated by the fact that diacetolol has some intrinsic sympathomimetic activity.     

Inhibition of synaptosomal [3H]noradrenaline uptake by beta-adrenoceptor blocking drugs: influence of lipophilicity

Ten beta-adrenoceptor blocking drugs varying in lipophilicity and beta-adrenoceptor blocking potency were examined for inhibitory effects on synaptosomal [3H]noradrenaline uptake. All compounds produced a concentration-dependent inhibition of noradrenaline uptake, but were at least one order of magnitude less potent than desmethylimipramine and cocaine. The order of potency was pronethalol greater than propranolol greater than betaxolol greater than alprenolol greater than oxprenolol greater than practolol greater than metoprolol greater than acebutolol greater than sotalol greater than atenolol, with IC50 values ranging from 4.0 X 10(-6) to 2.2 X 10(-3) M. Uptake inhibition was unrelated to beta-adrenoceptor blocking potency, but was highly correlated with drug lipophilicity. (+)-Propranolol was an effective uptake inhibitor, as was the local anaesthetic procaine. Kinetic analysis of uptake inhibition by propranolol, oxprenolol, metoprolol and procaine revealed a mixed inhibition for all four agents examined. It is suggested that this effect of beta-adrenoceptor blockers may be mediated, at least in part, by an action on membrane phospholipids associated with the noradrenaline carrier protein, and that noradrenaline uptake inhibition may underlie certain central side-effects observed with some drugs in this group.     

Blockade of isoprenaline-induced changes in plasma free fatty acids, immunoreactive insulin levels and plasma renin activity in healthy human subjects, by propranolol, pindolol, practolol, atenolol, metoprolol and acebutolol

1 The effects of intravenously administered propranolol 0.01 and 0.03, pindolol 0.001 and 0.003, practolol 0.12 and 0.36, atenolol 0.03 and 0.09, metoprolol 0.045 and 0.135 and acebutolol 0.12 and 0.36 mg/kg, on isoprenaline-induced changes in heart rate, blood pressure, plasma free fatty acids, immunoreactive insulin plasma levels and plasma renin activity were determined in six healthy human subjects.

2 Propranolol, atenolol and metoprolol had a stronger effect on resting heart rate than practolol, acebutolol and pindolol, probably reflecting differences in intrinsic β-sympathomimetic activity. Antagonist potencies against isoprenaline-induced changes in heart rate and blood pressure suggested cardioselectivity for practolol, atenolol, metoprolol and the lower dose of acebutolol and non-cardioselectivity for propranolol, pindolol and the higher dose of acebutolol.

3 All six β-adrenoceptor blocking agents were able, to a varying extent, to antagonize the isoprenaline-induced increases in plasma free fatty acids and plasma immunoreactive insulin levels. In general, the cardioselective agents were relatively less effective antagonists than the non-cardioselective agents.

4 Resting plasma renin activity was reduced by all six β-adrenoceptor blocking agents, suggestive of the presence of β₁-adrenoceptors mediating renin release, but the non-cardioselective agents propranolol and pindolol seemed relatively more effective in antagonizing isoprenaline-induced increases in plasma renin activity than the cardioselective agents, which indicates that β₂-adrenoceptors might also be involved.

5 The results are compatible with the hypothesis that both β₁- and β₂-adrenoceptors are involved in the regulation of lipolysis, insulin release and renin release.

     

Beta 1-selectivity of bisoprolol, a new beta-adrenoceptor antagonist, in anesthetized dogs and guinea pigs

The beta-adrenoceptor activity of the newly synthesized antagonist bisoprolol [+/-)-1-[4-(2-isopropoxyethoxymethyl)-phenoxy]-3-isopropylamino-2- propranol, hemifumarate), has been compared with the effect of several reference compounds in anesthetized dogs and guinea pigs. In anesthetized, bivagotomized dogs, isoprenaline dose-response relations for increase in heart rate and decrease in diastolic blood pressure were established. Bisoprolol had the largest beta 1/beta 2 ratio, i.e., 147 (102-292). Practolol showed a beta 1/beta 2 ratio greater than 17; betaxolol 6-15; acebutolol, atenolol, and metoprolol 1.1-3.2; mepindolol 0.6-1 and propranolol 0.2. In artificially ventilated guinea pigs, the activity of bisoprolol on histamine-induced increase in tracheal lateral pressure (TLP) and basal heart rate (HR) was tested: using doses taken at TLP (30 mm Hg) and HR (250 beats/min), bisoprolol exhibited the most pronounced ratio TLP/HR of 124 +/- 59, followed by atenolol 33 +/- 23, metoprolol 25 +/- 15, betaxolol 12 +/- 4, propranolol 1 +/- 0.3, and celiprolol 0.23 +/- 0.19. These experiments indicate that bisoprolol possesses a pronounced beta 1-selectivity, which seems to be superior to that of known beta 1-selective antagonists.     

Betaxolol, a cardioselective beta-adrenoceptor antagonist, attenuates ischemic myocardial acidosis in dogs

The effects of betaxolol, a cardioselective beta-adrenoceptor antagonist, on ischemic myocardial acidosis were studied in dog hearts, in which the left anterior descending coronary artery was partially occluded for 90 min, and were compared with those of atenolol and propranolol. Myocardial ischemia produced a decrease in myocardial pH (measured by a micro glass pH electrode) and an elevation of the ST segment of epicardial ECG (assessed by a surface electrode). Betaxolol (0.01, 0.03 or 0.1 mg/kg), atenolol (0.03 or 0.1 mg/kg) or propranolol (0.03 or 0.1 mg/kg), when injected i.v. 30 min after ischemia, restored myocardial pH and the ST segment of ECG that had been altered by partial occlusion. However, the effect of betaxolol on myocardial acidosis was more potent than that of atenolol or propranolol. The decrease in (+)dp/dt by betaxolol (0.03 mg/kg) was less potent than that by atenolol (0.1 mg/kg) and equivalent to that by propranolol (0.1 mg/kg), although the restorations of myocardial acidosis by the drugs were almost equivalent. These results have confirmed that beta-adrenoceptor antagonists attenuate the ischemia-induced myocardial acidosis and have shown that among three beta-adrenoceptor antagonists, betaxolol is the most effective in improving myocardial acidosis with a relatively weak effect on myocardial contractile function.     

Assessment of beta-adrenoceptor selectivity of a new beta-adrenoceptor antagonist, bisoprolol, in man

Bisoprolol is a new beta-adrenoceptor antagonist which has shown beta-adrenoceptor selectivity in studies in isolated tissues. Bronchial and cardiac beta-adrenoceptor blockade were assessed in eight normal subjects before and after oral ingestion of placebo, bisoprolol 20 and 40 mg, metoprolol 200 mg and propranolol 80 mg in random order. Bronchial beta-adrenoceptor blockade was assessed as the displacement of the bronchodilator dose-response curve to inhaled isoprenaline after each beta-adrenoceptor blocking drug compared to placebo and expressed as the dose ratio. Bronchodilatation was measured as change in specific airway conductance (sGaw) in the body plethysmograph. Cardiac beta-adrenoceptor blockade was assessed as the percentage reduction in exercise heart rate during the fifth minute of exercise at 70% of the subject's maximum work rate. Bisoprolol 20 and 40 mg caused a 24 and 25% reduction in exercise heart rate respectively, compared to 26% with metoprolol 200 mg and 20% with propranolol 80 mg. The dose ratios for the airway dose-response curves for the four beta-adrenoceptor blocking drugs were 1.04 and 3.4 for bisoprolol 20 and 40 mg, 1.4 for metoprolol 200 mg and 30 for propranolol 80 mg. Both doses of bisoprolol produced considerably less bronchial beta-adrenoceptor blockade than propranolol 80 mg despite causing a greater reduction in exercise heart rate. Bisoprolol 20 mg caused a similar amount of bronchial beta-adrenoceptor blockade and a similar reduction in exercise heart rate as metoprolol 200 mg, confirming that it is cardio-selective in man.     

Beta-adrenoceptor blocking effects and pharmacokinetics of betaxolol (SL 75212) in man.

1 The pharmacological effects and the pharmacokinetics of betaxolol (SL 75212), a new beta-adrenoceptor blocking agent, were compared with those of propranolol and a placebo in a double-blind trial involving six healthy volunteers. 2 Heart rate (HR), myocardial contractile force (MCF), systolic blood pressure (SBP) and peak expiratory flow rate (PEFR) were measured at rest and during vigorous exercise before and at intervals up to 25 h after oral administration of the drugs. In addition, plasma renin activity (PRA) at rest and blood levels of betaxolol and propranolol were determined. 3. Betaxolol proved to be a potent and long-lasting beta-adrenoceptor blocking drug, devoid of intrinsic beta-sympathomimetic activity. Its beta-adrenoceptor blocking action was shown to four-fold that of propranolol at the cardiac and renal levels and to last at least 25 h after drug intake. 4 The peak blood level of betaxolol was reached 2 to 4 hr after its administration, the first-pass loss is likely to be low and the half-life is 12.3 h. These pharmacokinetic data are perfectly consistent with the long duration of the pharmacological effects of betaxolol in man.     

Effects of ICI 141,292 on exercise tachycardia and isoprenaline-induced beta-adrenoceptor responses in man.

The beta-adrenoceptor blocking properties and cardioselectivity of ICI 141, 292 were investigated in healthy male subjects. Seven subjects received in random order oral doses of ICI 141,292 20, 50, 100, 200 and 400 mg, atenolol 50 and 100 mg and placebo. ICI 14 292 had no effect on supine heart rate which was reduced by atenolol 100 mg. ICI 141,292 50, 100 and 200 mg had no effect on standing heart rate which was reduced by 400 mg at 2 h. Both doses of atenolol caused greater reductions. The maximum percent reduction of an exercise tachycardia after ICI 141,292 200 mg (23.9 +/- 3.7%) and 400 mg (24.3 +/- 5.2%) were similar to atenolol 50 mg (27.3 +/- 4.7%) but less than atenolol 100 mg (30.8 +/- 2.9%) (P less than 0.02). Six subjects received in random order single oral doses of ICI 141,292 100, 200 and 400 mg, atenolol 50 mg, propranolol 40 mg and placebo. Following each dose each subject received graded infusions of isoprenaline sulphate until heart rate increased by 40 beats min-1. Dose-response curves were constructed for the changes in heart rate, finger tremor, blood pressure and forearm blood flow produced by each infusion. At the 4 micrograms min-1 dose of isoprenaline, ICI 141,292 200 mg caused more attenuation than atenolol 50 mg but less than propranolol 40 mg in the changes of heart rate, diastolic blood pressure and finger tremor (P less than 0.02). ICI 141,292 400 mg caused more attenuation of the changes of all parameters than atenolol 50 mg but less attenuation of the changes in diastolic blood pressure and finger tremor than propranolol 40 mg (P less than 0.02). These results indicate that ICI 141,292 is a cardioselective beta-adrenoceptor antagonist with partial agonist activity.     

Effects of betaxolol on cardiohemodynamics and coronary circulation in anesthetized dogs: comparison with atenolol and propranolol

Effects of betaxolol, a cardioselective beta-adrenoceptor antagonist, on cardiohemodynamics and coronary circulation were investigated in two kinds of anesthetized open-chest dog preparations in comparison with those of atenolol and propranolol. When administered intravenously, betaxolol, atenolol and propranolol produced dose-dependent decreases in the heart rate (HR), maximum left ventricular dP/dt [+)dP/dt), cardiac output (CO) and mean arterial pressure (MAP). Although all three drugs were almost equipotent in decreasing HR, betaxolol was much less potent than atenolol and propranolol in decreasing (+)dP/dt. Betaxolol decreased the total peripheral resistance (TPR), whereas atenolol and propranolol increased it. In another series of experiments, when administered intravenously, betaxolol, atenolol and propranolol all produced a decrease in the myocardial oxygen consumption (MVO2) and an increase in the atrioventricular conduction time (AVCT). All three drugs were nearly equipotent in decreasing MVO2, although betaxolol was less potent than the other two drugs at higher doses (greater than 300 micrograms/kg). Prolongation of AVCT with propranolol was stronger than those with betaxolol and atenolol. These results suggest that, unlike atenolol and propranolol, the decrease in TPR as well as beta 1-adrenoceptor blockade may be responsible for both the hypotensive effect of betaxolol and the decrease in MVO2 with betaxolol. The result that the cardiodepressant effect of betaxolol was much less potent than those of atenolol and propranolol suggests that betaxolol would be more beneficial than the others in the treatment of ischemic heart disease.     

Beta-adrenoceptor blockers and the blood-brian barrier.

1 This study on 21 neurosurgical patients was set up to investigate the extent to which four chronically administered beta-adrenoceptor blockers, propranolol, oxprenolol, metoprolol and atenolol, cross and blood-brain barrier and enter the cerebrospinal fluid (CSF) and brain tissue. The concentration in the CSF of the three lipophilic beta-adrenoceptor blockers, propranolol, oxprenolol and metoprolol, approximated to the free drug concentration in the plasma, and was a poor predictor of brain concentration. These three lipophilic beta-adrenoceptor blockers appeared in brain tissue at concentrations 10-20 times greater than that of hydrophilic atenolol. The approximate brain/plasma ratio for propranolol was 26, for oxprenolol 50, for metoprolol 12 and for atenolol 0.2. 2 The low concentration of atenolol in brain tissue is possibly responsible for the low incidence of central nervous system-related side effects in patients on this agent compared to lipophilic beta-adrenoceptor blockers.     

Betaxolol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in hypertension

Betaxolol is a relatively cardioselective beta-adrenoceptor blocking drug, with no partial agonist (intrinsic sympathomimetic) activity and weak membrane-stabilising (local anaesthetic) activity. Its pharmacokinetic properties of most interest include high bioavailability after oral administration, and a long elimination half-life. It has a narrow dose-response range, which obviates the need for dose titration, with 10 to 20 mg once daily being the usual dosage. This dose reduces systolic and diastolic blood pressures by about 15 mm Hg in most patients with mild to moderate hypertension. In a few comparative studies betaxolol 20 mg daily was as effective as atenolol and moderate doses of propranolol, and more effective than acebutolol, in reducing blood pressure in such patients. Betaxolol has been well tolerated in most patients. Thus, betaxolol is an effective alternative to other beta-blocking drugs in patients with essential hypertension, with properties that may offer advantages in some patients.     

β-ADRENOCEPTOR MEDIATED SECRETION OF ACTIVE AND INACTIVE RENIN IN CONSCIOUS SHEEP

1. Beta-adrenoceptor linked regulation of plasma active and inactive renin was investigated in sheep with indwelling artery, vein and bladder catheters. Concurrent changes in renal function were also monitored. 2. The beta-adrenoceptor agonist isoprenaline (bolus intravenous (i.v.) dose 0.5 mg/kg, 0.05 microgram/kg per min) increased plasma active renin concentration within 15 min and reached a plateau increase of 306%. Initially plasma inactive renin remained unchanged but after 105 min it decreased. 3. The non-selective beta-adrenoceptor antagonist propranolol (bolus i.v. dose 4 mg/kg, 40 micrograms/kg per min) did not significantly alter basal plasma active renin but selectively reduced inactive renin. The absence of any change in active renin may reflect the relatively low level of stress-induced sympathetic activation in these conscious animals compared to equivalent studies carried out on human subjects. 4. Using the same dose schedules, propranolol completely blocked the isoprenaline-induced increases in plasma active renin secretion even though it had no effect on the basal active renin levels. 5. The selective beta 1-adrenoceptor antagonist atenolol (bolus i.v. dose 5 mg/kg) decreased basal plasma active renin by 24% (+ 135 min) but reduced plasma inactive renin by 75% compared to control. 6. Therefore, both a beta-adrenoceptor agonist (isoprenaline) and two beta-adrenoceptor antagonists (propranolol and atenolol) decreased plasma inactive renin concentration in conscious sheep. 7. These results are discussed in relation to the accompanying changes in arterial blood pressure and aspects of renal function.     

The selectivity of the beta-adrenoceptor for ventilation in man.

1 Minute ventilation, alveolar PCO2, CO2 production and heart rate were measured in eight normal subjects before and during infusions of noradrenaline 0.2, 1.0 and 5.0 micrograms min-1 and isoprenaline 0.04, 0.2 and 1.0 microgram min-1. 2 These measurements were repeated after propranolol 3.5 mg, atenolol 8 mg or metoprolol 7 mg by intravenous injection. 3 Noradrenaline 5.0 micrograms min-1 and isoprenaline 1.0 microgram min-1 significantly increased ventilation and CO2 production and decreased alveolar PCO2. These changes were attenuated by propranolol, atenolol and metoprolol. There was no significant difference between the blocking effects of the three beta-adrenoceptor blockers for these three variables but propranolol was more effective than atenolol or metoprolol in blocking isoprenaline induced tachycardia (P less than 0.001). 4 The hyperventilatory response to catecholamines is predominantly a beta1-effect.     

Inhibition of nicotine-induced relaxation of the bovine retractor penis muscle by beta-adrenoceptor antagonists.

The relative potency in inhibiting nicotine-induced relaxation of the bovine retractor penis muscle (BRP) was estimated for the racemates of seven beta-adrenoceptor antagonists, both of the optical isomers of propranolol, and lidocaine. The order of potency of the drugs studied was (+)-propranolol greater than (-)-propranolol greater than propranolol greater than alprenolol greater than metoprolol greater than lidocaine greater than acebutolol greater than pindolol greater than sotalol greater than atenolol. It is concluded that the inhibition of the relaxation was not due to blockade of beta-adrenoceptors but to the nonspecific effects of the beta-adrenoceptor antagonists. It is also concluded that the neurotransmitter(s) which was (were) released from the non-adrenergic non-cholinergic inhibitory nerves in the BRP did not relax the muscle by activating the beta-adrenoceptors. It is suggested that the beta-adrenoceptor antagonists inhibited the release of the inhibitory neurotransmitter(s) by a mechanism which is significantly correlated to their lipophilicity.     

Beta-adrenoceptor blockade and hypoglycaemia. A randomised, double-blind, placebo controlled comparison of metoprolol CR, atenolol and propranolol LA in normal subjects.

1. The effect of 1 week of treatment with propranolol LA (160 mg), atenolol (100 mg) and metoprolol CR (100 mg) on awareness of and the physiological responses to moderate hypoglycaemia were compared with placebo using a randomised, cross-over design in 12 healthy volunteers. 2. All three beta-adrenoceptor antagonists reduced resting heart rate, systolic blood pressure and heart rate responses to submaximal exercise compared with placebo. 3. Under hyperinsulinaemic (60 mu m-2 min-1) clamp conditions, at a blood glucose of 2.5 mmol l-1, atenolol prevented the rise in systolic and atenolol and metoprolol CR prevented the fall in diastolic blood pressure usually associated with hypoglycaemia. At this level of hypoglycaemia, the expected increase in heart rate was inhibited by atenolol but not metoprolol CR. Pre-treatment with propranolol LA resulted in a significant pressor response and a bradycardia during hypoglycaemia. In addition the normal increase in finger tremor was abolished by propranolol LA. 4. During hypoglycaemia all three beta-adrenoceptor blockers augmented sweating compared with placebo but hypoglycaemic symptoms, awareness and slowing of reaction time were the same with drugs and placebo. 5. The rise in plasma adrenaline and other counter-regulatory hormones during hypoglycaemia was enhanced by beta-adrenoceptor blockade. 6. We conclude that beta-adrenoceptor antagonists modify the physiological and hormonal responses to, but do not adversely affect awareness of, moderate hypoglycaemia in healthy volunteers.     

Steady-state fluctuation and variability of betaxolol and atenolol plasma levels

Twenty-four nonsmoking male volunteers took 50 mg atenolol or 10 mg betaxolol orally once a day for 9 days in a two-period, four-sequence, randomized, crossover study. Plasma concentrations reached steady state after day 5. Percent fluctuation in plasma concentration defined as (Cmax-Cmin)/Cavg (% fluctuation 1) was 97% on day 9 for betaxolol and 343% for atenolol; thus atenolol fluctuation was more than threefold that of betaxolol. A 10-fold difference in plasma level fluctuation was observed when fluctuation was defined as (Cmax-Cmin)/Cmin (% fluctuation 2). The intersubject variances for % fluctuation 1 and % fluctuation 2 were 4.1 and 85.5 times greater for atenolol than for betaxolol; these differences were marginally statistically significant for % fluctuation 1 and significant for % fluctuation 2. The intrasubject variabilities for area under the curve and plasma level fluctuations were statistically greater for atenolol than for betaxolol. Atenolol intrasubject variances were 25 and 271 times greater than for betaxolol for % fluctuation 1 and % fluctuation 2, respectively. Thus, betaxolol exhibited less fluctuation in plasma levels with substantially less intersubject and intrasubject variability. These factors would be expected to provide a more consistent therapeutic response and more dependable dosage adjustment.     

Plasma levels and beta-adrenoceptor blockade with acebutolol, practolol and propranolol in man.

1 The degree of beta-adrenoceptor blockade of isoprenaline-induced tachycardia has been determined in three healthy volunteers after the administration of single oral doses of acebutolol, practolol or propranolol. 2 Plasma levels of these drugs were determined either colorimetrically (acebutolol and practolol) or fluorimetrically (propranolol). The colorimetric assay of acebutolol in plasma is fully described but the other drugs were assayed by published methods. 3 The degree of beta-adrenoceptor blockade and the plasma level for acebutolol and practolol were well correlated, whereas in the case of propranolol correlation was poor, due in part to the presence in plasma of active metabolites not detected by the fluorimetric assay. The plasma levels of practolol and propranolol are in agreement with those previously reported. 4 The maximum cardiac beta-adrenoceptor blockade achieved in this study with the respective single oral doses of acebutolol (300 mg), practolol (400 mg) or propranolol (40 mg) were similar in each of the three subjects. Therefore the beta-adrenoceptor blocking potencies of these drugs against isoprenaline-induced tachycardia are inversely related to these doses; indicating that propranolol is 7-8 times more potent than acebutolol and the latter slightly more potent than practolol.     

A dose ranging study of atenolol in hypertension: fall in blood pressure and plasma renin activity, beta-blockade and steady-state pharmacokinetics.

The relationship between the oral dosage and plasma concentration of the long-acting cardioselective beta-adrenoceptor blocker atenolol and the antihypertensive response to the the degree of beta-adrenoceptor blockade and change in plasma renin activity (PRA) was evaluated in patients with mild-to-moderate essential hypertension in a double-blind, randomized, between-patient, dose-ranging (25, 50 or 100 mg once daily for 4 weeks) study. The optimum, or minimum, daily dose of atenolol to treat patients with mild-to-moderate hypertension was not clearly identified in this study. A between-treatment comparison did not demonstrate that all blood pressure falls were always less in the 25 mg group than in the other two groups. Calculation of beta-error or the power for the negative results between doses suggested that a large sample size is required to draw a conclusion that no dose-antihypertensive relationship of atenolol exists in the treatment of mild-to-moderate hypertension. A relatively flat plasma concentration-antihypertensive response relationship was observed. Steady-state plasma concentrations of atenolol were dose-related and renal drug clearance was well correlated with individual creatinine clearance. beta-adrenoceptor blockade was better correlated with plasma atenolol concentration. Correlations which were less strong were between plasma drug concentration and change in various blood pressures and between blood pressure falls and beta-adrenoceptor blockade. There was no relationship between the fall in blood pressure and change in PRA. Atenolol appeared to suppress PRA in an all-or-none fashion.     

Observation on the efficacy and pharmacokinetics of betaxolol (SL 75212), a cardioselective beta-adrenoceptor blocking drug.

1 Observations were made in five subjects who exercised before and at 2, 3, 6, 8, 24, 33 and 48 h after the oral administration of placebo and 5, 10, 20 and 40 mg betaxolol. 2 The exercise heart rate remained constant at all times after the placebo. All doses of betaxolol significantly reduced the exercise tachycardia at all times. The maximum effect (34.4 +/- 2.2%) occurred after 40 mg. 3 There was a small decline in effect from the peak to 24 h when 40 mg produced a 23.3 +/- 2.7% reduction and a further decline to 48 h when there was a 14.6 +/- 1.8% reduction. 4 Plasma levels of betaxolol were measured in these studies. The peak plasma concentration occurred between 3 and 8 h with different doses. The plasma elimination half-lives after 10, 20 and 40 mg were 11.4 +/- 2.5, 15.9 +/- 4.9 and 15.1 +/- 3.1 h. 5 The effects of 40 mg betaxolol, 200 mg atenolol, 160 mg propranolol, 160 mg oxprenolol, 400 mg sotalol and placebo on an exercise tachycardia were compared in five subjects who received all treatments in random order. 6 There was no significant difference in the maximum reduction produced in an exercise tachycardia by the different drugs. 7 The effect of all drugs decreased with time. The effect of oxprenolol had worn off at 24 h but at 48 h only atenolol and betaxolol produced significant reductions in the exercise tachycardia. 8 Plasma concentrations of the different drugs were measured and plasma elimination half-lives determined. The half-life for betaxolol was 24.5 h which was longer than that for any of the other drugs. 9 These observations show that betaxolol is a potent beta-adrenoceptor antagonist with a long duration of effect on an exercise tachycardia and a long plasma elimination half-life.     

The assessment of the beta-adrenoceptor blocking activity and cardioselectivity of Koe 3290 in normal subjects.

1. The beta-adrenoceptor antagonist activity, cardioselectivity and antilipolytic properties of Koe 3290 were investigated in healthy subjects. 2. Koe 3290 12.5, 25, 50 and 100 mg, atenolol 25, 50 and 100 mg and placebo were given in double-blind randomised order to eight subjects. All doses of both Koe 3290 and atenolol reduced supine, standing and exercise heart rate (P less than 0.02). From 2 to 8 h after administration the exercise heart rate after Koe 3290 100 mg was similar to that for atenolol 50 mg. 3. The cardioselectivity of Koe 3290 and atenolol was compared. Koe 3290 50, 100 and 150 mg, atenolol 50 and 100 mg and placebo were given to six subjects in a double-blind random order. Isoprenaline dose-response curves were constructed for cardiovascular parameters and finger tremor. 4. For doses which were equipotent at the beta 1-adrenoceptor (Koe 3290 100 mg and atenolol 50 mg) atenolol caused less attenuation of heart rate, diastolic blood pressure, forearm blood flow and finger tremor (P less than 0.02). 5. There was no difference in the isoprenaline-induced changes in serum free fatty acids, blood glucose, plasma lactate or potassium after Koe 3290 and atenolol. Koe 3290 attenuated the rise in serum insulin more than atenolol (P less than 0.02). 6. Koe 3290 is an effective beta-adrenoceptor blocking drug in man. It is not as cardioselective as atenolol and does not possess specific antilipolytic properties.