Beta-adrenoceptor blockade by atenolol, metoprolol and propranolol in the anaesthetized cat.

The inhibitory effects of atenolol, metoprolol and propranolol on isoprenaline-induced tachycardia, broncho-relaxation and vasodilatation were investigated in the reserpinized and anaesthetized cat. In low doses all three antagonists inhibited the heart rate response to isoprenaline, the order of potency being propranolol greater than metoprolol greater than atenolol. While propranolol inhibited the bronchodilation and vasodilation responses to isoprenaline in the same dose range as it blocked the heart rate response, atenolol and metoprolol had to be given in considerably higher doses to block these effects. The results indicate that both metoprolol and atenolol, in contrast to propranolol, are selective beta1-adrenoceptor antagonist. No statistically significant difference in the degree of selectivity was found between metoprolol and atenolol. The three compounds were devoid of intrinsic beta-mimetic activity.     

A comparison of the pharmacokinetics of atenolol, metoprolol, oxprenolol and propranolol in elderly hypertensive and young healthy subjects.

Six elderly patients with established hypertension and six young healthy subjects were studied after 8 days of treatment with atenolol 50 mg day-1, metoprolol 50 mg day-1, oxprenolol 80 mg day-1 and propranolol 80 mg day-1. The area under the blood concentration-time curve was increased in the elderly group for each drug, but the difference was statistically significant only for atenolol. The lower serum albumin concentrations in the elderly group did not result in a decrease in the percentage of propranolol or oxprenolol bound to serum proteins.     

Pharmacodynamic comparison of L-bunolol with propranolol, metoprolol, and placebo

Twelve healthy volunteers received single oral doses of propranolol (80 mg), metoprolol (100 mg), L-bunolol (2 mg), and placebo in a four-way crossover study. Blood pressure, ventricular rate, and echocardiographically determined ejection fraction, ejection time, and mean rate of circumferential fiber shortening (mVcf) were measured before dosing and at multiple time points during 10 hours after each dose, with subjects maintained in the supine position. Reductions in systolic and diastolic blood pressure following administration of each of the beta blockers were greater than those observed with placebo, but differences among the four treatments were not significant. Heart rate reductions with the beta blockers differed significantly from placebo (P less than .001), but differences among the three beta blockers were not significant. Differences among the four treatments in mVcf decrement did not attain significance at the 5% level (.05 less than P less than .1), and there were no significant differences in ejection-time prolongation or ejection-fraction reduction. Thus, reduced blood pressure, heart rate slowing, and reduced cardiac contractility may be associated with placebo treatment and may indicate the need for placebo controls in studies of the cardiovascular effects of beta blockers. Despite differing secondary pharmacologic properties, the three beta blockers reduced heart rate to a similar extent. Other effects of the beta blockers on blood pressure and cardiac contractility could not be consistently distinguished from those associated with placebo.     

Comparison of atenolol and propranolol during insulin-induced hypoglycaemia.

The effects of atenolol, a new beta1-blocking drug, on pulse rate, sweating, and blood glucose levels during insulin-induced hypoglycaemia were studied in a double-blind crossover trial in eight normal subjects using placebo and propranolol as reference agents. The intensity of induced hypoglycaemia was identical for atenolol, propranolol, and placebo. Propranolol prolonged hypoglycaemia, but atenolol did not. Atenolol may therefore be safe for use in patients receiving insulin.     

Comparison of propranolol, metoprolol, and acebutolol on insulin-induced hypoglycaemia.

Metoprolol and acebutolol, two supposedly cardio-selective beta-adrenergic recptor blocking agents, were tested in healthy volunteers against propranolol, a non-selective drug, for their effect on blood glucose levels during insulin-induced hypoglycaemia. There was not significant difference between propranolol and metoprolol, which both potentiated the initial hypoglycaemic action of the insulin and delayed the return to normoglycaemia. Acebutolol, even though potentiating the initial hypoglycaemia, did not possess a significant delaying effect. A similar trial should be undertaken in diabetics to determine with certainty the safety of such drugs in diabetes mellitus.     

Psychotropic effects of repeated doses of enalapril, propranolol and atenolol in normal subjects.

1 Enalapril 20 mg, propranolol 160 mg, atenolol 50 mg and placebo each were given once a day for 8 days to 12 normal volunteers, using a Latin-square design and double-blind procedures. A battery of tests was applied before, 2 and 4 h after the dose on day 1 and 8. 2 EEG effects were detected on day 8 with propranolol but not consistently after atenolol or enalapril. 3 Reaction-time, symbol copying and memory were impaired with propranolol; only memory was marginally affected by atenolol. Enalapril impaired memory but improved tapping ability. 4 Subjectively, propranolol was associated with drowsiness, enalapril with calmness and perhaps contentedness. Ratings of headache were increased with enalapril. 5 It is concluded that the apparent beneficial subjective effects of enalapril in clinical practice are attributable partly to intrinsic central effects but mainly to the contrast with beta-adrenoceptor blockers such as propranolol.     

CNS-related subjective symptoms during treatment with beta 1-adrenoceptor antagonists (atenolol, metoprolol): two double-blind placebo controlled studies.

1. Whilst a number of studies have investigated whether metoprolol and atenolol, the most widely used beta 1-adrenoceptor antagonists, differ with regard to CNS-related subjective symptoms, few placebo-controlled studies using standardised questionnaires have been performed. 2. In the present report, the findings of two randomised, double-blind, cross-over studies in healthy volunteers are presented. The subjects were treated with placebo and atenolol (100 mg once daily) (Study 1) and metoprolol (100 mg once daily) and placebo (Study 2). 3. Subjective experiences were evaluated using a standardised instrument, the Minor Symptoms Evaluation-profile (MSE-profile), which was filled in 4, 8 and 24 h after intake of the tablets. A Type A questionnaire was also completed by the subjects. 4. At 4 h both metoprolol and atenolol were found to affect negatively vitality and contentment, but these effects had declined after 8 h. A significant adverse effect on sleep was shown for atenolol compared with placebo, while no negative effect was observed for metoprolol. No significant differences were found in relation to Type A behaviour and beta-adrenoceptor blockade. The number of subjects with Type A personality was, however, low. 5. The results of the studies indicate that the subjective symptoms of the beta 1-adrenoceptor blockers are mild, and that the effects appear consistently with the recognised pharmacokinetic profiles of the two drugs.     

Exercise metabolism in healthy volunteers taking atenolol, high and low doses of metoprolol CR/Z0K, and placebo.

1. Exercise and beta-adrenoceptor blockade have important roles in the prevention and treatment of cardiovascular disease, but fatigue and a reduced capacity to exercise are commonly reported side effects of beta-adrenoceptor blockers. The reduced capacity to exercise may be partly caused by a reduction in fat metabolism. 2. We investigated the effects of atenolol 50 mg, metoprolol CR/Z0K 50 mg, metoprolol CR/Z0K 100 mg and placebo, on heart rate, energy expenditure, fat oxidation, plasma free fatty acids, glycerol, glucose, lactate, ammonia and perceived exertion during 2 h of treadmill walking at 40% of maximal oxygen uptake in 20 healthy volunteers. 3. Compared with placebo (38.0%), total fat oxidation was significantly lower on atenolol 50 mg (30.1%) and metoprolol CR/Z0K 100 mg (31.0%), but not on metoprolol CR/Z0K 50 mg (33.7%). Reductions in fat oxidation correlated well (r2 = 0.970) with reductions in exercising heart rate, and probably reflected the degree of beta 1-adrenoceptor blockade. Maximum plasma ammonia concentration was reached after 45 min of exercise on atenolol, 60 min on metoprolol CR/Z0K 100, and 75 min on metoprolol CR/Z0K 50, and was higher than placebo on all active drug treatments. 4. The greater reduction in fat oxidation with atenolol may be a reflection of a peak in plasma concentration, which is avoided with a controlled release preparation.     

Acebutolol, atenolol, and propranolol and metabolic responses to acute hypoglycaemia in diabetics.

In a double-blind crossover study the symptomatic and metabolic effects of propranolol, acebutolol, and atenolol were studied during insulin-induced hypoglycaemia in diabetics treated with diet or hypoglycaemic tablets. All the drugs prevented tachycardia, but did not affect the other symptoms of hypoglycaemia. Propranolol delayed the recovery of the blood glucose concentration and impaired the secondary rise in the concentrations of blood lactate and non-esterified fatty acids in diet-treated diabetics. Acebutolol potentiated the hypoglycaemic effect of insulin in tablet-treated diabetics (mean difference of blood glucose concentration 0.7 mmol/l (12.6 mg/100 ml)) and this difference was maintained during the recovery phase4 the blood lactate response was also impaired. Atenolol did not differ perceptibly from placebo in its effect on the metabolic responses to acute hypoglycaemia. The results may be explained by differences in the known pharmacological actions of these drugs. They support the hypothesis that beta-adrenoreceptor blocking drugs that are highly beta1 specific and without membrane-stabilising activity should be safer than the non-selective drugs when used in diabetic patients at risk from hypoglycaemia.     

A placebo controlled comparison of the effects of metoprolol and celiprolol on echo-Doppler measurements of cardiovascular function in normal volunteers.

1. This study used a continuous-wave echo-Doppler method (Exerdrop) to investigate the effects of beta-adrenoceptor antagonism and partial agonism on cardiovascular responses at rest and during dynamic exercise. 2. A double-blind, randomised, placebo controlled comparison of metoprolol (50 mg) and celiprolol (200 mg) was undertaken in nine normal volunteers; single oral doses of medication were administered at weekly intervals. Rest and exercise (supine bicycle) haemodynamics were assessed at 0, 2, 4, 6 and 8 h following dosing. 3. Before dosing and after placebo, the aortic flow velocity, acceleration and velocity integral increased progressively during exercise, as did heart rate, blood pressure and cardiac output. 4. Following metoprolol 50 mg, heart rate was significantly reduced without change in systolic or diastolic blood pressure. Echo-Doppler peak acceleration and velocity decreased at rest. On exercise, heart rate and systolic blood pressure fell significantly; the increase in acceleration was significantly blunted compared with placebo (a decrease of 15.2% at rest and 22.9% at 75 watts; P < 0.01 vs placebo). Peak velocity fell significantly by 75 watts exercise. 5. Celiprolol 200 mg at rest significantly increased systolic blood pressure, peak acceleration and velocity. On exercise celiprolol, in contrast to metoprolol, did not reduce peak acceleration or peak velocity; however exercise heart rate and systolic blood pressure were significantly reduced. The difference between celiprolol and metoprolol in respect of peak acceleration persisted over the 8 h of the study. 6. These differences between metoprolol and celiprolol are compatible with the partial agonism of celiprolol.(ABSTRACT TRUNCATED AT 250 WORDS)     

The short term effects of propranolol, atenolol and labetalol on antipyrine kinetics in normal subjects.

1 The effects of three day courses of propranolol 40 mg three times daily, atenolol 100 mg twice daily and labetalol 100 mg three times daily on antipyrine kinetics were examined in 13 normal subjects. 2 The mean antipyrine clearance initially was 41.3 +/- 12.4 ml/min (mean +/- s.d.) and fell to 35.0 +/- 12.1 ml/min following propranolol (P less than 0.025), 34.5 +/- 9.5 ml/min following atenolol (P less than 0.01), and 35.2 +/- 8.6 ml/min following labetalol (P less than 0.05). 3 The prolongation in antipyrine half-life was significant only following atenolol. Propranolol only caused a significant reduction in the volume of distribution of antipyrine. 4 These adrenoceptor antagonists appear to decrease antipyrine clearance in normal subjects. The reduction in antipyrine clearance was similar with all three drugs and appeared to be independent of the differing lipid solubilities and pharmacological profiles of the adrenoceptor antagonists examined.     

Effect of diltiazem on the pharmacokinetics of propranolol,metoprolol and atenolol

Summary The pharmacokinetic interaction between diltiazem and three -adrenoceptor blockers propranolol, metoprolol and atenolol was investigated in healthy volunteers given diltiazem 30 mg or placebo t.d.s. for 3 days, followed by a single dose of propranolol 20 mg, metoprolol 40 mg or atenolol 50 mg.The AUCs of propranolol and metoprolol were significantly increased after diltiazem and it significantly prolonged the elimination half-life of metoprolol. In contrast, it did not significantly affect the pharmacokinetics of atenolol. Propranolol significantly decreased the resting pulse rate after diltiazem pretreatment as compared to placebo.The results indicate that diltiazem impaired the clearance of propranolol and metoprolol, which are principally metabolized by an oxidative pathway, and that the kinetic interaction between diltiazem and propranolol may partly be related to the significant reduction in the pulse rate produced by the latter.     

Gas chromatographic-mass spectrometric differentiation of atenolol, metoprolol, propranolol, and an interfering metabolite product of metoprolol

Over a 10-year period, 1993-2002, Federal Aviation Administration identified 50 pilot fatalities involving atenolol, metoprolol, and propranolol, which is consistent with the fact that these drugs have been in the lists of the top 200 drugs prescribed in the U.S. In a few of the 50 pilot fatality cases, initial analysis suggested the presence of atenolol and metoprolol. However, there was no medical history with these cases supporting the use of both drugs. Therefore, atenolol, metoprolol, and/or propranolol, with their possible metabolite(s), were re-extracted from the selected case specimens, derivatized with pentafluoropropionic anhydride (PFPA), and analyzed by gas chromatography-mass spectrometry (GC-MS). The MS spectra of these three antihypertensives and a metoprolol metabolite are nearly identical. All of the PFPA derivatives had baseline GC separation, with the exception of a metoprolol metabolite product, which co-eluted with atenolol. There were four primary mass fragments (m/z 408, 366, 202, and 176) found with all of the PFPA-beta-blockers and with the interfering metabolite product. However, atenolol has three unique fragments (m/z 244, 172, and 132), metoprolol has two unique fragments (m/z 559 and 107), propranolol has four unique fragments (m/z 551, 183, 144, and 127), and the metoprolol metabolite product has two unique fragments (m/z 557 and 149). These distinctive fragments were further validated by using a computer program that predicts logical mass fragments and performing GC-MS of deuterated PFPA-atenolol and PFPA-propranolol and of the PFPA-alpha-hydroxy metabolite of metoprolol. By using the unique mass fragments, none of the pilot fatality cases were found to contain more than one beta-blocker. Therefore, these mass ions can be used for differentiating and simultaneously analyzing these structurally similar beta-blockers in biological samples.     

Influence of hyperthyroidism on the kinetics of methimazole,propranolol, metoprolol and atenolol

Summary The kinetic profiles of oral methimazole 40mg, propranolol 80mg, metoprolol 100mg and atenolol 100mg were compared in hyperthyroid patients both during the hyper-and euthyroid states. For methimazole, neither the peak concentration (C_max), the time to reach peak concentration (t_max), the elimination half-life (t_1/2) nor the area under the curve (AUC) value was affected by the hyperthyroid state. For propranolol and metoprolol, which undergo extensive presystemic clearance, the AUC values were lower (p<0.02) when the patients were hyperthyroid than when they had become euthyroid, but the t_1/2's were not significantly altered. For atenolol, there were no significant kinetic differences between the hyperthyroid and euthyroid states. The findings are compatible with the assumption that hyperthyroidism does not affect the kinetics of methimazole or atenolol, but that it may enhance presystemic clearance of propranolol and metoprolol.     

Debrisoquine polymorphism and the metabolism and action of metoprolol,timolol, propranolol and atenolol

1. The contribution of debrisoquine polymorphism to the metabolism and action of β-adrenoceptor antagonists (β-blockers) varies widely between drugs.

2. Oxidation phenotype is a major determinant of the metabolism, pharmacokinetics and some of the pharmacological actions of metoprolol, bufuralol and timolol. The poor metabolizer phenotype is associated with an increased area under the plasma drug concentration vs. time curve, a prolongation of elimination half-life and a more intense and sustained β-blockade.

3. The stereoselective metabolism of metoprolol also displays phenotypic differences, which should be taken into account when interpreting plasma concentration vs. response relationships.

4. Studies in vivo and in vitro have identified some of the metabolic pathways which are subject to this defect, namely the α-hydroxylation and the O-demethylation of metoprolol and the 1′-hydroxylation of bufuralol.

5. In contrast, the pharmacokinetics and pharmacodynamics of propranolol, which is also extensively oxidized, are not related to debrisoquine polymorphism, although 4′-hydroxypropranolol formation is deficient in the poor metabolizer phenotype.

6. The disposition of atenolol, which is almost completely eliminated unchanged by renal and faecal excretion, is independent of oxidation phenotype.

7. If standard doses of some β-blockers are used in poor metabolizers, these patients may be susceptible to concentration-related adverse reactions and they may also require lower and less frequent dosing for control of angina pectoris.     

Debrisoquine polymorphism and the metabolism and action of metoprolol, timolol, propranolol and atenolol

The contribution of debrisoquine polymorphism to the metabolism and action of beta-adrenoceptor antagonists (beta-blockers) varies widely between drugs. Oxidation phenotype is a major determinant of the metabolism, pharmacokinetics and some of the pharmacological actions of metoprolol, bufuralol and timolol. The poor metabolizer phenotype is associated with an increased area under the plasma drug concentration vs. time curve, a prolongation of elimination half-life and a more intense and sustained beta-blockade. The stereoselective metabolism of metoprolol also displays phenotypic differences, which should be taken into account when interpreting plasma concentration vs. response relationships. Studies in vivo and in vitro have identified some of the metabolic pathways which are subject to this defect, namely the alpha-hydroxylation and the O-demethylation of metoprolol and the 1'-hydroxylation of bufuralol. In contrast, the pharmacokinetics and pharmacodynamics of propranolol, which is also extensively oxidized, are not related to debrisoquine polymorphism, although 4'-hydroxypropranolol formation is deficient in the poor metabolizer phenotype. The disposition of atenolol, which is almost completely eliminated unchanged by renal and faecal excretion, is independent of oxidation phenotype. If standard doses of some beta-blockers are used in poor metabolizers, these patients may be susceptible to concentration-related adverse reactions and they may also require lower and less frequent dosing for control of angina pectoris.     

A double-blind comparison of nefopam and placebo in post-operative pain.

Nefopam (90 mg), an analgesic, was compared with placebo in a double-blind trial in patients who had undergone total abdominal hysterectomy operations. Analgesic activity was assessed by patients rating their pain before and 1 hour after administration of each treatment, by sequential analysis of patient and observer preference for treatment, and by calculation of the time interval between doses of the two treatments. Nefopam was found by observer preference to be significantly better than placebo in relieving post-operative pain. In patients with severe initial pain, the time between doses after nefopam was significantly longer than after placebo.     

Single-dose kinetics of oral propranolol, metoprolol, atenolol, and sotalol: relation to lipophilicity

Nine healthy volunteers received single oral doses of the following four beta-adrenergic blocking agents: propranolol (160 mg), metoprolol (100 mg), atenolol (200 mg), and sotalol (320 mg). The kinetics of each drug were determined from multiple serum concentrations measured during 24-48 h after each dose, and in vitro lipid solubility determined using the liquid chromatographic (HPLC) retention index. Oral clearance for the four drugs ranged from 40.2 ml/min/kg for propranolol down to 2.1 for sotalol. Oral clearance was highly correlated (r = 0.99) with in vitro lipid solubility, with propranolol being the most lipophilic drug and sotalol the least. Thus lipophilicity is a physicochemical property of beta-adrenergic blockers that appears to influence their intrinsic clearance after oral dosage.