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.     

Antihypertensive effect of a non-selective (propranolol) and a cardioselective (metoprolol) beta-adrenoceptor blocking agent at rest and during exercise.

1 The antihypertensive effects at rest and during physical exercise of the non-selective beta-adrenoceptor blocker propranolol and the cardioselective beta-adrenoceptor blocker metoprolol were compared in a double-blind cross-over study. 2 Eighteen patients with mild hypertension entered the trial. One patient was withdrawn from the study due to side effects on both drugs. 3 The two beta-adrenoceptor blockers were compared using doses earlier shown to have the same beta-adrenoceptor blocking potency, as measured by their effect on exercise tachycardia in healthy men. 4 Arterial blood pressure was reduced to the same extent by propranolol and metoprolol at rest as well as during submaximal work. 5 It is concluded that the antihypertensive effect of beta-adrenoceptor blockers is mainly mediated through blockade of the beta 1-adrenoceptors.     

Metoprolol and propranolol treatment in carbon tetrachloride-induced hepatic injury.

The effects of beta 1-selective metoprolol (CAS 37350-58-6) and the nonselective beta-adrenoceptor antagonist propranolol (CAS 525-66-6) were investigated in healthy and CCl4 damaged male rats. Treatments were performed for 16 days, orally with dosages reducing heart beat/min by 25% (metoprolol 10 mg/kg, propranolol 1 mg/kg). Liver glycogen content was not influenced by either beta-blocker in healthy animals. CCl4-induced loss of glycogen was equally moderated by metoprolol and propranolol. Blood glucose increased in metoprolol treated healthy and liver damaged rats after a single dosage likewise following prolonged treatment. Propranolol was without effect on blood glucose level. Cytochrome P-450 decline in microsomal fraction was greater in metoprolol, than in propranolol treated healthy animals. However, the severe fall elicited by liver injury was moderated by metoprolol and normalised by propranolol. Cytochrome b5 seems to be involved in metoprolol metabolism. Cytochrome P-450-dependent aminopyrine-N-demethylase was impeded by metoprolol in animals with healthy liver. The serious inhibition caused by CCl4 was moderated by metoprolol and with a better result by propranolol. The high serum bilirubin level in liver lesion was lowered by metoprolol and particularly by propranolol. Neither phase I metabolic process aminopyrine-N-demethylation nor phase II glucuronidation were normalised. A comparison of this data with the results of a previous 12-day treatment schedule indicates that no changes in efficacy occurred with longer treatment. The present results pertain to the importance of the selection of beta-adrenoceptor blocker in liver lesion.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of acute or chronic ingestion of propranolol or metoprolol on the metabolic and hormonal responses to prolonged, submaximal exercise in hypertensive men.

We have studied the effects of single oral doses of, and of 28 days treatment with, placebo, propranolol or metoprolol, on the metabolic and hormonal responses to prolonged exercise in hypertensive men. Blood glucose levels fell during exercise on all occasions. No additional effects of the beta-adrenoceptor antagonists, compared to placebo, were observed. The exercise-induced increase in plasma potassium was enhanced after a single dose of propranolol or metoprolol, and also after chronic treatment with propranolol. Chronic treatment with either drug led to an increase in plasma potassium levels at rest. The growth hormone response to exercise was potentiated by a single dose of metoprolol or propranolol, and after chronic treatment with the drugs. A single dose of propranolol (but not metoprolol) was associated with a marked increase in plasma cortisol and adrenaline levels during exercise. After chronic treatment no such increase occurred. In both the acute and chronic phases of the study, blood lactate levels were higher during exercise in the presence of either propranolol or metoprolol compared to placebo, whereas non-esterified fatty acid levels were lower. A single dose of metoprolol produced a significantly greater reduction in blood glycerol levels during exercise than a single dose of propranolol. After chronic treatment, both propranolol and metoprolol produced similar reductions in blood glycerol levels during exercise. After a single dose, both drugs significantly augmented the increase in plasma noradrenaline levels during exercise. A similar effect was seen after chronic treatment.     

Failure of 'therapeutic' doses of beta-adrenoceptor antagonists to alter the disposition of tolbutamide and lignocaine.

The effects of separate 1 week pre-treatments with each of the beta-adrenoceptor antagonists, propranolol (80 mg every 12 h), metoprolol (100 mg every 12 h) and atenolol (50 mg once daily), on the disposition of a single i.v. dose of tolbutamide were studied in six healthy volunteers. In addition, the effects of a 1 week pre-treatment with metoprolol (100 mg every 12 h) and atenolol (50 mg once daily) on the disposition of orally and i.v. administered lignocaine were determined in seven healthy subjects. Tolbutamide clearance, half-life, volume of distribution and plasma protein binding were not altered by the beta-adrenoceptor blocker pre-treatments. Similarly, neither metoprolol nor atenolol had a significant effect on the systemic clearance, apparent oral clearance or other dispositional parameters of lignocaine. 'Therapeutic' plasma concentrations of the beta-adrenoceptor blockers were confirmed on each study day. It is concluded that the inhibition of oxidative drug metabolism previously reported for lipophilic beta-adrenoceptor blockers may be selective for different forms of cytochrome P450 and possible concentration-dependent.     

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.     

Can the biochemical responses to a beta 2-adrenoceptor stimulant be used to assess the selectivity of beta-adrenoceptor blockers?

The extent to which beta-adrenoceptor blocking drugs counteract the biochemical responses to an infusion of terbutaline, a beta 2-adrenoceptor agonist, has been investigated. In this study the beta 1-selectivity of metoprolol was compared with the non-selective beta-adrenoceptor blocker propranolol. The hypokalaemia produced by an infusion of terbutaline was reduced by low dose (50 mg) and high dose (200 mg) metoprolol and by low dose (40 mg) and high dose (160 mg) propranolol. The effects of propranolol on terbutaline induced hypokalaemia were more marked than those of metoprolol at both low dose (P = 0.01) and high dose (P = 0.05). Furthermore low dose metoprolol had less effect than high dose metoprolol (P = 0.05). The serum potassium appeared to rise slightly after propranolol. Low and high doses of both beta-adrenoceptor blockers markedly reduced the terbutaline-induced hyperglycaemia, but the differences between the two drugs were not statistically significant.     

Acebutolol, metoprolol and propranolol in conscious dogs with chronic heart-block: chronotropic effects and relation between depression of ventricular activity and beta-adrenoceptor blocking potency.

1 Atrial and ventricular chronotropic effects of acebutolol, metoprolol and propranolol were studied in conscious dogs with chronic heart-block. Ventricular beta-adrenoceptor blocking activity was assessed for the three dogs against isoprenaline (1 microgram/kg) under the same experimental conditions. 2 Acebutolol and metoprolol significantly increased atrial rate. The effect was proportional to the dose for acebutolol, independent for metoprolol. Propranolol had no significant effect on atrial rate. All three drugs significantly lowered ventricular rate in proportion to the dose. 3 Ventricular beta-blocking potencies of metoprolol and acebutolol were respectively 2 and 3 times weaker than that of propranolol as indicated by ED50 values. 4 The ventricular depressor effect observed was proportional to the degree of ventricular beta-blockade present, although this may not be the only factor involved.     

Influence of β-adrenoceptor antagonists on the pharmacokinetics of rizatriptan, a 5-HT1B/1D agonist: differential effects of propranolol, nadolol and metoprolol

AIMS: Patients with migraine may receive the 5-HT1B/1D agonist, rizatriptan (5 or 10 mg), to control acute attacks. Patients with frequent attacks may also receive propranolol or other beta-adrenoceptor antagonists for migraine prophylaxis. The present studies investigated the potential for pharmacokinetic or pharmacodynamic interaction between beta-adrenoceptor blockers and rizatriptan. METHODS: Four double-blind, placebo-controlled, randomized crossover investigations were performed in a total of 51 healthy subjects. A single 10 mg dose of rizatriptan was administered after 7 days' administration of propranolol (60 and 120 mg twice daily), nadolol (80 mg twice daily), metoprolol (100 mg twice daily) or placebo. Rizatriptan pharmacokinetics were assessed. In vitro incubations of rizatriptan and sumatriptan with various beta-adrenoceptor blockers were performed in human S9 fraction. Production of the indole-acetic acid-MAO-A metabolite of each triptan was measured. RESULTS: Administration of rizatriptan during propranolol treatment (120 mg twice daily for 7.5 days) increased the AUC(0, infinity) for rizatriptan by approximately 67% and the Cmax by approximately 75%. A reduction in the dose of propranolol (60 mg twice daily) and/or the incorporation of a delay (1 or 2 h) between propranolol and rizatriptan administration did not produce a statistically significant change in the effect of propranolol on rizatriptan pharmacokinetics. Administration of rizatriptan together with nadolol (80 mg twice daily) or metoprolol (100 mg twice daily) for 7 days did not significantly alter the pharmacokinetics of rizatriptan. No untoward adverse experiences attributable to the pharmacokinetic interaction between propranolol and rizatriptan were observed, and no subjects developed serious clinical, laboratory, or other significant adverse experiences during coadministration of rizatriptan with any of the beta-adrenoceptor blockers. In vitro incubations showed that propranolol, but not other beta-adrenoceptor blockers significantly inhibited the production of the indole-acetic acid metabolite of rizatriptan and sumatriptan. CONCLUSIONS: These results suggest that propranolol increases plasma concentrations of rizatriptan by inhibiting monoamine oxidase-A. When prescribing rizatriptan to migraine patients receiving propranolol for prophylaxis, the 5 mg dose of rizatriptan is recommended. Administration with other beta-adrenoceptor blockers does not require consideration of a dose adjustment.     

Synthesis of a series of compounds related to betaxolol, a new beta 1-adrenoceptor antagonist with a pharmacological and pharmacokinetic profile optimized for the treatment of chronic cardiovascular diseases

A series of para-substituted phenoxypropanolamines has been synthesized and tested for beta-adrenoceptor blocking activity. Some derivatives (8, 11, 12, 20, 21) exhibited greater in vitro potency than the reference drugs metoprolol and propranolol. This series, in contrast to propranolol but similar to metoprolol, possesses cardioselectivity. The 3-[p-[(cycloalkylmethoxy)ethyl]phenoxy]-1-substituted-amino-2-prop anol derivatives 8 (cyclopropylmethoxyethyl: betaxolol) and 11 (cyclobutylmethoxyethyl) produced antihypertensive effects in spontaneously hypertensive rats. Betaxolol (Kerlon, 8) was found to exhibit an appropriate preclinical pharmacological and human pharmacokinetic profile (elevated oral bioavailability and prolonged plasma half-life) for the treatment of chronic cardiovascular diseases such as hypertension and angina.     

The effects of acute or chronic ingestion of propranolol or metoprolol on the physiological responses to prolonged, submaximal exercise in hypertensive men

We have studied the physiological responses to 50 min of intermittent, moderate exercise in hypertensive men after the ingestion of a single dose of placebo, propranolol or metoprolol, and also after 28 days treatment. In addition, subjective assessments of mood were made during the last 7 days of each period of chronic treatment. Heart rate and blood pressure, both at rest and during exercise, were significantly reduced by a single dose of propranolol or metoprolol; more marked effects were observed after chronic treatment. Ventilation and gas exchange during exercise were only slightly disturbed by single doses of propranolol or metoprolol, whereas chronic treatment had no effect. Perceived exertion scores were increased after a single dose of either drug, compared to placebo, and the effect of propranolol was greater than that of metoprolol. With chronic treatment there were fewer differences between the perceived exertion scores during exercise, although 'leg' fatigue remained greater after propranolol than after placebo. Sweating from the forehead during exercise was enhanced by a single dose of either beta-adrenoceptor antagonist, with propranolol having the greater effect. After chronic treatment the effect of propranolol was diminished, whereas the effect of metoprolol was maintained. Very few disturbances of mood were found after chronic ingestion of the beta-adrenoceptor antagonists.     

Alterations in blood levels of carbohydrate and lipid metabolites and of cyclic AMP mediated by beta1- and beta2-adrenoceptors in beagle dogs: effects of procaterol, a new selective beta2-adrenoceptor agonist.

The intravenous injection of isoprenaline (10 nmole/kg) into conscious beagle dogs caused significant increases in the blood level of lactate, glucose, FFA, insulin and cyclic AMP. These metabolic alterations induced by isoprenaline were blocked completely by pretreatment of the dog with propranolol (1 mg/kg). Butoxamine (10 mg/kg) antagonized isoprenaline-induced increases in glucose, lactate and insulin, but not the increases in FFA. Practolol (10 mg/kg) diminished the increase in blood FFA very strongly. Salbutamol, which is known to be an agonist of the beta 2-subtype in its bronchomotor and cardiovascular actions, produced marked increases in the blood concentrations of lactate, glucose and insulin but were without effect on the FFA level. Thus metabolic responses of conscious beagle dogs to beta-adrenoceptor agonists appeared to depend differentially on two types of beta-adrenoceptors: beta1-adrenoceptors are largely involved in lipolysis while beta2-adrenoceptors are involved in the regulation of blood glucose metabolism and insulin secretion. A new beta-adrenoceptor agonist, 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril hydrochloride hemihydrate (Procaterol), was classified as a beta 2-agonist, because it markedly increased plasma concentrations of glucose, lactate and insulin but increased the plasma level of FFA to a lesser degree. The order of potency of beta2-agonists was procaterol greater than salbutamol greater than trimetoquinol. Metabolic responses of beagle dogs would be useful for appreciating the selectivity and potency of beta-adrenoceptor agonists and antagonists.     

Inhibition of antipyrine metabolism by beta-adrenoceptor antagonists.

1 The effects of two beta-adrenoceptor antagonists (propranolol and metoprolol), and of the beta-adrenoceptor agonist, terbutaline, on the plasma kinetics of antipyrine were studied in five normal subjects. In addition, the influence of propranolol on the clearance of antipyrine to three of its major metabolites was investigated. 2 At the same level of beta-adrenoceptor blockade, assessed by lowering of exercise tachycardia, propranolol decreased antipyrine clearance by 37.3 +/- 9.9 s.d. % (P less than 0.001) and metoprolol decreased it by 18.0 +/- 4.7 s.d. % (P less than 0.01). Terbutaline had no effect on antipyrine clearance. The volume of distribution of antipyrine was unchanged following treatment with all three drugs. 3 Only the metabolic clearance of antipyrine to its 3-hydroxymethyl product was impaired to a statistically significant degree by propranolol. However, four of the five subjects also showed impaired clearance to 4-hydroxyantipyrine and three of the five to norantipyrine after propranolol treatment. In four of the five subjects propranolol lowered the renal clearance of antipyrine. 4 Inhibition of the metabolism of antipyrine by beta-adrenoceptor antagonists may be related to their lipid-solubility and extent of metabolism and is independent of their effect on beta-adrenoreceptors.     

Effects of cold exposure on blood pressure, heart rate and forearm blood flow in normotensives during selective and non-selective beta-adrenoceptor blockade.

Haemodynamic effects of a cold pressor test (foot immersion for 6 min in water at 5 degrees C) without medication and after the non-selective beta-adrenoceptor blocker propranolol and the selective beta-adrenoceptor blocker metoprolol were studied in 17 volunteers. In the control study as well as in the study with the beta-adrenoceptor blockers cold exposure caused comparable changes, namely a blood pressure rise and a reduction of forearm blood flow. The increase in heart rate during cold exposure was clearly and equally reduced by both beta-adrenoceptor blockers. Plasma noradrenaline rose significantly by 47%, plasma adrenaline did not change. It is concluded, that as to this kind of stress, beta 1-selective-adrenoceptor blockade confers no important advantage over non-selective beta-adrenoceptor blockade.     

Inhibition of purified lysosomal phospholipase A1 by beta-adrenoceptor blockers

Inhibition of rat liver lysosomal phospholipases is one of the main events that leads to accumulation of tissue phospholipids during drug-induced phospholipidosis. Drug inhibition of lysosomal phospholipase A may occur by direct effects of drugs on the enzyme (or substrate) or by drug-induced increases in intralysosomal pH. Although beta-adrenoceptor blockers have not been reported to cause lipid storage, they do inhibit lysosomal phospholipase A. To investigate the structural requirements for drug inhibition, we studied the effects of six beta-adrenoceptor blockers on purified rat liver lysosomal phospholipase A1. The agents studied include: propranolol, timolol, metoprolol, practolol, atenolol and the combined alpha and beta adrenoceptor blocking agent, labetalol. The drugs varied by two logs in their abilities to inhibit phospholipase A1 activity. The relative inhibitory potencies were propranolol greater than labetalol much greater than timolol greater than metoprolol much greater than practolol greater than atenolol. Our studies identify drug hydrophobicity as a key determinant for phospholipase A1 inhibition. A strong negative correlation was noted between the octanol/water partition coefficients and IC50 for phospholipase inhibition (r = -0.91). The ability of propranolol to inhibit phospholipase A1 was identical for the d, l and the d and l stereoisomers.     

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.     

The effects of propranolol and metoprolol on skin blood flow in diabetic patients.

The effect of 2 weeks treatment with propranolol or metoprolol on skin blood flow (SBF) at rest was examined in 12 diabetic patients with essential hypertension in whom gross large vessel disease had been excluded. Neither drug significantly altered resting skin blood flow. However we cannot exclude an important difference between the two beta-adrenoceptor blockers because of the great variability of SBF within subjects. A larger study and/or more accurate methods of measuring SBF are needed to determine if beta 1-selective adrenoceptor antagonists differ from non-selective beta-adrenoceptor blockers with respect to skin blood flow.     

The effect of acebutolol and propranolol on the hypoglycaemic action of glibenclamide.

1 The effect of acebutolol, a relatively selective beta-adrenoceptor blocking drug and propranolol, a non-selective one, on the hypoglycaemic action of glibenclamide after an oral glucose load has been investigated in a group of maturity-onset diabetic patients. 2 Glibenclamide significantly reduced the blood glucose levels and both acebutolol and propranolol, at therapeutic doses, were found to modify this action significantly. 3 The effect of acebutolol was slightly less than that of propranolol. The difference was not statistically significant. 4 The modes of action of sulphonylureas are reviewed and it is suggested that beta-adrenoceptor blockers may modify their effect on insulin release. This appears to be a drug interaction rather than an effect of beta-adrenoceptor blockade on glucose tolerance.     

L-dopa, growth hormone and adipokinesis in the lean and the obese.

Fourteen human volunteers (5 lean of both sexes, 4 grossly obese male, 4 grossly obese female, and one patient suffering from hypopituitarism) were given 500 mg of L-dopa orally, and growth hormone (HGH), cortisol, prolactin (hPRL), insulin, FSH, LH, free fatty acids (FFA) and blood glucose were determined up to 300 minutes following the drug. The lean group showed a uniformly marked increase in HGH followed by a significant FFA rise. The obese females exhibited blunted HGH and a somewhat reduced FFA response. In the obese male, there were no HGH und FFA increments. Unstimulated levels of HGH were lower and FFA markedly higher in both obese male and female vs the lean group. The patient with hypopituitarism showed no significant HGH and FFA response. In all groups, hPRL decreased, while Cortisol, LH, FSH, and blood glucose levels remained uninfluenced.     

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.