An alternative, simple method to assess beta 1-selectivity is to establish the impact of the beta blocker on beta 2-stimulated increases in plasma glucose and decreases in plasma potassium during an intravenous infusion of terbutaline. In the present study the effects of metoprolol CR/ZOK 100 mg, conventional metoprolol 100 mg, atenolol 100 mg, and placebo on these biochemical changes have been compared. In 12 healthy volunteers, terbutaline infusion of 6 micrograms/kg was administered intravenously over 1 hour. Three and a half hours before the infusion they were given a single dose of each of the four treatments in random order, single-blind. The maximum increase in plasma above baseline occurred at the end of a 60-minute terbutaline infusion. All three-beta blockers decreased the peak plasma glucose level achieved compared with placebo (P less than .01) but this reduction was significantly less with metoprolol CR/ZOK pretreatment than with atenolol (P less than .05). Similar results were seen for the AUC values for the curves obtained from the increments over the 60 minutes of the infusion and the subsequent 120 minutes after the infusion. In addition, both the AUC values and the maximum fall in potassium were significantly reduced by all treatments (P less than .05). The metoprolol CR/ZOK preparation produced significantly less effect than atenolol with respect to both AUC (P less than .05) and maximum fall (P less than .01) and significantly less effect than conventional metoprolol tablets in maximum fall (P less than .01). In conclusion, the metoprolol CR/ZOK formulation produces lower plasma concentrations and results in less effect on potassium and glucose compared to conventional metoprolol and atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)
SUMMARY The impact of cimetidine, ranitidine and placebo on the pharmacokinetics of metoprolol, given either as a single dose (100 mg) or for 7 days (100 mg b.d.), has been evaluated in two separate studies. The doses used were 800 mg cimetidine daily and 300 mg ranitidine daily. The subjects were all young, healthy volunteers. In the single dose study, cimetidine produced a marked increase in the peak plasma concentration of metoprolol and in the area under the plasma concentration‐time curve; ranitidine had less effect, though the area under the curve was significantly greater than placebo. In the chronic dosing study, the area under the curve for metoprolol was also significantly higher on cimetidine (1796 ng h/ml; P < 0.001) whereas the area under the curve on ranitidine (1258 ng h/ml) was comparable to that on placebo (1183 ng h/ml). Despite these drug‐induced changes in plasma metoprolol concentration, neither cimetidine nor ranitidine altered the change in exercise‐induced heart rate during dosing with metoprolol.
We have investigated the beta-1 selectivity of a new beta-blocker, Bisoprolol, by comparing its effect on lipolysis induced by intravenous terbutaline infusion with that of Atenolol. At a dose of 5 mg, Bisoprolol had virtually no beta-2 blocking activity as measured by free fatty acid (FFA) release during terbutaline infusion. At a dose of 10 mg, Bisoprolol had a small but statistically insignificant effect on FFA release similar to 50 mg Atenolol. At a dose of 20 mg, Bisoprolol had significant beta-2 blocking activity. At lower doses, therefore, Bisoprolol is a very selective beta-blocker.
This paper reports on a randomized double-blind crossover study to compare the effects of daily treatment with 100 mg conventional metoprolol (M100), 50 or 100 mg slow-release metoprolol CR (CR50, CR100) and placebo on the response to treadmill walking exercise in 12 healthy volunteers. Twenty minutes of exercise was undertaken at 1.5 h post-dose (Ex1) and again at 4 h (Ex2). During Ex1 all metoprolol preparations caused a reduction in the exercise-induced increase in heart rate when compared to placebo (P < 0.001). The exercise-induced increase in plasma glycerol, an indicator of lipolysis, was diminished by all metoprolol preparations but to a greater extent by M100 (P < 0.05). Rises in plasma ammonia were used to assess the net degradation of energy-rich adenine nucleotides by skeletal muscle during exercise. When compared to placebo, a significant elevation in plasma ammonia was seen only during exercise with M100 (P < 0.05). The perceived exertion at the end of exercise was also greatest on conventional metoprolol. The differences between the effects of conventional and CR formulations of metoprolol were less when exercise was repeated 4 h post dosing. We conclude that metoprolol CR may offer advantages over the conventional preparation, in subjects regularly engaging in exercise, by reducing the metabolic stress imposed upon skeletal muscle.
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