Human pharmacokinetic and pharmacodynamic studies on the atenolo (ICI 66,082), a new cardioselective beta‐adrenoceptor blocking drug.

Bronchial and cardiac beta‐adrenoceptor blockade have been compared in six normal subjects after three beta‐adrenoceptor antagonists. Single and double doses of atenolol (50 and 100 mg), acebutolol (100 and 200 mg) and labetalolol (150 and 300 mg) were studied on separate occasions. 2 Salbutamol airway dose‐response curves were obtained by measuring the airway response as the change in specific airway conductance (sGaw) after increasing doses of inhaled salbutamol. Bronchial beta‐adrenoceptor blockade was assessed after each drug as the dose of salbutamol needed to cause a 50% increase in sGaw (sGaw D50). 3 Cardiac beta‐adrenoceptor blockade was assessed after the same doses of each beta‐adrenoceptor antagonist, by measuring the percentage reduction in exercise heart rate from control, after exercise for 5 min at 70% of the subject's maximum work rate. 4 Atenolol 50 and 100 mg caused least bronchial beta‐adrenoceptor blockade and the greatest reduction in exercise heart rate. 5 Acebutolol 100 and 200 mg and labetalol 150 and 300 mg produced more bronchial beta‐adrenoceptor blockade than atenolol. 6 With this approach new beta‐adrenoceptor antagonists can be assessed without putting asthmatic patients at risk.

Section: Discussionmentioning

confidence: 99%

Bronchial and cardiac beta‐adrenoceptor blockade‐a comparison of atenolol, acebutolol and labetalol.

Gribbin¹,

Mackay²,

Baldwin³

et al. 1981

“…(0) propranolol. Atenolol, the PI-selective adrenoceptor antagonist, had a smaller but nevertheless significant effect on both of these parameters even at a dose of 25 mg; such an effect on diastolic pressure has been reported previously (Conway et al, 1976). Forearm blood flow has been used previously in the assessment of Padrenoceptor antagonists, with either intraarterial isoprenaline (Brick et al, 1968;Briant et al, 1973), or intravenous bolus injections (Mougeot et al, 1981;.…”

Section: Studymentioning

confidence: 99%

Effects of the beta 2‐adrenoceptor antagonist ICI 118,551 on exercise tachycardia and isoprenaline‐induced beta‐adrenoceptor responses in man.

Arnold¹,

O'Connor²,

Riddell³

et al. 1985

ICI 118,551, 5 to 80 mg orally, did not significantly alter resting heart rate or blood pressure. In doses less than 40 mg the reduction in exercise tachycardia was under 10 beats/min. ICI 118,551, 10 to 40 mg, did not appear to reduce the maximum rise in systolic pressure with isoprenaline but did attenuate the changes in diastolic pressure, forearm blood flow and finger tremor. It also attenuated the isoprenaline‐induced changes in serum glucose, insulin and potassium. On these observed changes, the effect of ICI 118,551 20 mg was similar to that of 40 mg and of propranolol 10 mg, but greater than that of atenolol 25 mg. An isoprenaline tachycardia was attenuated by all doses of ICI 118,551 studied. After atropine (0.04 mg/kg) ICI 118,551 20 mg still significantly reduced the effects of isoprenaline suggesting that functional beta 2‐adrenoceptors may be present in the human heart. In doses less than 40 mg, ICI 118,551 appears to be a selective and competitive antagonist of beta 2‐adrenoceptors in man.

“…Identical placebo tablets to atenolol 50 mg and propranolol 40 mg were used, so that a total of five tablets were given on each day. Pharmacokinetic studies with atenolol have shown that peak plasma levels occur within 2 to 3 h of oral dosing (Conway et al, 1976;Brown et al, 1976;Fitzgerald et al, 1978), and subjects therefore attended the laboratory 3 h after drug ingestion. sGaw was measured 15 min after each dose increment.…”

Section: Protocolmentioning

confidence: 99%

Assessment of airways, tremor and chronotropic responses to inhaled salbutamol in the quantification of beta 2‐adrenoceptor blockade.

Lipworth

Brown

McDevitt

1989

1 The purpose of the study was to assess and compare the effects of inhaled salbutamol on heart rate (HR), finger tremor (Tr) and specific airways conductance (sGaw) in the measurement of 32-adrenoceptor blockade in normal subjects. 2 Five healthy volunteers were given oral doses of atenolol 50 mg, 100 mg, 200 mg (AS0, A100, A200), propranolol 40 mg (P40) or identical placebo (P1) in a single-blind crossover design. 3 Three hours after drug ingestion, dose-response curves were constructed using cumulative doses of inhaled salbutamol: 200 ,g, 700,ug, 1700 ,ug, 3200 ,ug, 6200,ug. HR, Tr and sGaw were measured at each dose increment, made every 20 min. 4 Increasing doses of atenolol were associated with progressive reduction in salbutamol induced ,-adrenoceptor responses. The greatest attenuation occurred with propranolol. These effects on ,B-adrenoceptor responses were similar for HR, Tr and sGaw. Geometric mean dose ratios (compared with placebo) for AS0, A100, A200 and P40 were as follows HR: 1.98, 2.75, 4.29; Tr: 1.60, 3.78, 6.34, 80.50; sGaw: 1.08, 4.35, 12.30, 66.0 (no dose ratio was obtained for HR with P40). 5 These results showed that atenolol and propranolol attenuated the effects of salbutamol on HR to a similar degree as Tr and sGaw. Furthermore, the variability was least in the measurement of chronotropic responses, suggesting that this may be used to quantify 132-adrenoceptor antagonism. The B1-adrenoceptor selectivity of atenolol was a dosedependent phenomenon, although the 132-adrenoceptor blockade of A200 was much less than with P40.