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Purpose: To compare the co-prescription of metoprolol and potent CYP2D6-inhibiting antidepressants before and during a 10-year period after implementation of an optimized drug interaction database into clinical decision support systems in Norway. Methods: The study was a retrospective, cross-sequential nationwide analysis of drug-dispensing data retrieved from the Norwegian Prescription Database over a 1-year period before (2007) and two 1-year periods after (2012 and 2017) implementation of a drug interaction database providing recommendations on non-interacting alternative medications. Primary outcome was changes in co-prescription rates of metoprolol and the potent CYP2D6-inhibiting antidepressants fluoxetine, paroxetine, or bupropion relative to alternative antidepressants with no or limited CYP2D6 inhibitory potential. To control for potential secular trend bias, a comparison group consisting of atenolol/bisoprolol users was included. Results: The co-prescription rate of metoprolol with potent CYP2D6 inhibitors declined following implementation of the optimized database, by 21% (P < 0.001) after 5 years and by 40% (P < 0.001) after 10 years. Compared with atenolol/bisoprolol users, patients treated with metoprolol had significantly reduced likelihood of being prescribed a CYP2D6-inhibiting antidepressant in the two post-implementation periods (OR 0.61 (95% CI 0.54–0.69) and OR 0.45 (95% CI 0.40–0.51), respectively, versus OR 0.84 (95% CI 0.74–0.94) prior to implementation). Small and mostly insignificant differences in average daily metoprolol dosage were found between patients treated with the various antidepressants. Conclusion: The present study suggests that implementation of a drug interaction database providing recommendations on non-interacting drug alternatives contributes to reduced co-prescribing of drug combinations associated with potentially serious adverse effects. [ABSTRACT FROM AUTHOR]

The sphingosine-1-phosphate receptor modulator fingolimod (FTY720) is known to elicit a negative chronotropic effect at treatment initiation that attenuates over time with continued dosing. The authors determined the effect of combining a single dose of fingolimod with steady-state atenolol or diltiazem on heart rate and mean arterial pressure. In a partially randomized, single-blind, placebo-controlled, three-period, crossover study, 25 healthy subjects received (1) a single oral 5-mg dose of fingolimod, (2) either 50 mg atenolol or 240 mg diltiazem once daily for 5 days, and (3) the antihypertensive for 5 days and a single dose of fingolimod on day 5. Telemetry and pharmacokinetic data were collected. The daytime mean heart rate nadir was 15% lower when fingolimod was combined with atenolol (42 ± 7 bpm) compared with fingolimod alone (51 ± 9 bpm) yielding a combination/monotherapy ratio of 0.85 (90%CI, 0.79–0.92). The daytime mean heart rate nadir from fingolimod alone (55 ± 5 bpm) was not altered when combined with diltiazem (56 ± 8 bpm) yielding a ratio of 0.99 (0.94–1.05). There was no clinically relevant change in mean arterial pressure when fingolimod was administered with atenolol or diltiazem compared with administration of the drugs alone in normotensive subjects. The pharmacokinetics of the drugs were not altered during coadministration. Adding fingolimod to a beta-blocker such as atenolol resulted in a moderately lower mean heart rate nadir compared with fingolimod alone. However, subjects who had a stronger negative chronotropic response to fingolimod alone (nadir < 50 bpm) had minimal or no further reduction in heart rate with the drug combination. Adding fingolimod to a calcium channel blocker such as diltiazem did not further lower the heart rate compared to fingolimod alone. [ABSTRACT FROM AUTHOR]

Objective: Fruit juices can significantly change the pharmacokinetics of several drugs. Our objective was to investigate the effect of orange juice on the pharmacokinetics of the beta-blocking agent atenolol. Methods: In a randomized cross-over study with two phases and a washout of 2 weeks, ten healthy volunteers took either 200 ml orange juice or water thrice daily for 3 days and twice on the fourth day. On the morning of day 3, each subject ingested 50 mg atenolol with an additional amount of either 200 ml orange juice or water. The plasma concentrations of atenolol and the cumulative excretion of atenolol into urine were measured up to 33 h after its dosing. Systolic and diastolic blood pressures and heart rate were recorded in a sitting position before the intake of atenolol and 2, 4, 6, and 10 h after. Results: Orange juice decreased the mean peak plasma concentration (Cmax) of atenolol by 49% (range 16-59%, P<0.01), and the mean area under the plasma atenolol concentration-time curve (AUC0-33 h) by 40% (range 25-55%, P<0.01). The time of the peak concentration (tmax) and the elimination half-life (t1/2) of atenolol remained unchanged by orange juice. The amount of atenolol excreted into urine was decreased by 38% (range 17-60%, P<0.01), but the renal clearance remained unaltered. The average heart rate was slightly higher during the orange juice+atenolol phase than during the water+atenolol phase. Conclusions: Orange juice moderately interferes with the gastrointestinal absorption of atenolol. This food-drug interaction can be of clinical significance. [ABSTRACT FROM AUTHOR]

Objective. To compare the effects of valsartan and atenolol on sexual activity and plasma testosterone in newly diagnosed, previously untreated, essential hypertensive male subjects. Methods. One hundred and ten hypertensive men, aged 40–49 years, homogeneous for marital status and without any previous sexual dysfunction were randomly treated with valsartan 80 mg daily (o.d.) or atenolol 50 mg o.d. for 16 weeks according to a double-blind, parallel-arm study design. After 8 weeks the dose was doubled in the non-responders (diastolic blood pressure >90 mmHg). Clinical evaluation was performed after 8 weeks and 16 weeks of treatment and included blood pressure and plasma testosterone measurements and the compilation of a questionnaire about sexual activity (sexual intercourse episodes/month). Results. Despite similar blood pressure lowering, atenolol significantly reduced sexual activity (from 6.0 sexual intercourse episodes/month to 4.2 sexual intercourse episodes/month, P<0.01 vs placebo), whereas valsartan increased it, although not significantly (from 5.8 sexual intercourse episodes/month to 7.4 sexual intercourse episodes/month, P=0.058), compared with placebo, but significantly compared with the atenolol group (P<0.05). Testosterone was reduced by atenolol (from 18.2 nmol/l to 13.8 nmol/l, P<0.01 vs baseline) but was not affected by valsartan (from 17.6 nmol/l to 18.3 nmol/l). Conclusions. These results suggest that atenolol induces a worsening of sexual activity and a reduction of testosterone, whereas valsartan does not worsen sexual activity and does not change testosterone levels. [ABSTRACT FROM AUTHOR]

Objective: Partial gastric resection alters the anatomy and secretory activity of the gastrointestinal tract. It might be expected that the consequences of such changes should affect the pharmacokinetics, especially concerning the absorption of orally administered drugs. Propranolol and atenolol, as representatives of lipophilic and hydrophilic β-adrenoreceptor antagonists, have been studied in order to define their pharmacokinetic characteristics in patients after partial gastrectomy. Methods: The study was carried out in 29 patients after gastric resection with Billroth I (B1) anastomosis and in 18 healthy volunteers as controls. Pharmacokinetics of propranolol and atenolol was investigated after a single oral dose of 80 mg and 100 mg, respectively, following a cross-over schedule. Blood samples were collected ten times during the 24 h after the drug administration. Pharmacokinetic parameters of propranolol and atenolol were calculated using a one-compartment open model with first-order absorption. Results: The average blood plasma concentrations of propranolol in gastrectomised patients were lower than those in controls, reaching significance between 1.5 h and 6.0 h of the observation period. Pharmacokinetic parameters of propranolol were different in subjects submitted to surgery compared with healthy persons. We observed a significant decrease in the area under the concentration–time curve (32%) and the peak plasma concentration (20%), and an increase in half-life (25%). Mean plasma concentrations and pharmacokinetic parameters of atenolol in patients following partial gastric resection were not significantly different from those in the controls. No relationship between time interval following partial gastrectomy and pharmacokinetic parameters of the investigated drugs was noted. Conclusion: Partial gastrectomy with B1 anastomosis affects the pharmacokinetics of propranolol (lipophilic drug) but not atenolol (hydrophilic drug). [ABSTRACT FROM AUTHOR]

This double-blind, randomised, within patient, placebo-controlled study set out to investigate the effect of a cardioselective beta-blocker, atenolol, at different oral doses (50, 100 and 200 mg) and a non-selective agent, propranolol (40 mg), upon 1. airways resistance (forced expiratory volume at one second=FEV) and 2. the bronchodilator action of increasing doses of inhaled isoprenaline, in patients with co-existent hypertension and reversible airways obstruction. In 10 patients, two hours after drug administration, the 3 doses of atenolol caused a significantly greater ( P<0.05) degree of B-blockade than propranolol. In contrast the 3 doses of atenolol caused significantly less ( P<0.05 to 0.01) B-blockade as evidenced by a smaller fall in FEV. The isoprenaline FEV dose response curves were displaced progressively to the right of the placebo curve with increasing doses of atenolol, but the greatest displacement was with propranolol. It was concluded that patients with reversible airways obstruction who require beta-blockade should be given a low dose of a cardioselective agent in conjunction with, if required, a beta stimulant such as isoprenaline. Such a treatment will be less likely to cause a troublesome increase in airways resistance and the bronchodilator action of the beta stimulant will be almost fully preserved. [ABSTRACT FROM AUTHOR]

Serum lipoproteins were determined in 15 patients before and during antihypertensive treatment with atenolol 0.1-0.2 g/day for a mean of 8 months. The mean blood pressure fell from 171/103 to 154/93 mm Hg ( p<0.05). Significant lipoprotein changes were an increase in very low density triglycerides (VLDL-TG) from 1.21±0.95 (SD) to 1.62±1.24 mmol/l ( p<0.01) and in low density (LDL) TG from 0.46±0.12 to 0.51±0.12 mmol/l ( p<0.05). Together, these TG increases resulted in development of hypertriglyceridaemia in 7/15 patients during atenolol treatment. No effect on whole serum cholesterol or on the high density lipoprotein cholesterol concentrations were found. Thus, some patients on long term treatment with atenolol seem to receive the benefit of normotension at the cost of hypertriglyceridaemia. This may have practical implications, since hypertriglyceridaemia constitutes an important risk factor for atherosclerosis. [ABSTRACT FROM AUTHOR]

Atenolol 100 mg and penbutolol 40 mg given once a day were both effective in controlling moderate hypertension, as judged by a randomised controlled, double-blind trial in 45 patients treated for six weeks. Both drugs significantly reduced the resting supine and erect blood pressures. No serious adverse effects could be attributed to either drug. Bradycardia occurred more frequently with atenolol than with penbutolol. Penbutolol, which possesses intrinsic sympathomimetic activity, may be useful in the treatment of patients in whom some other beta-blocker has failed to bring about adequate control of the blood pressure, despite marked bradycardia. [ABSTRACT FROM AUTHOR]

A double blind, placebo-controlled study of the ventilatory effects of three new beta-selective adrenoceptor blockers was carried out in eight asthmatic patients. Measurements were performed before and 2, 3 and 4 h after ingestion of a single oral dose of placebo, atenolol 100 mg, metoprolol 100 mg or acebutolol 400 mg. At each time ventilatory indices and heart rate were assessed before, during and 15 min after an exercise test. The ventilatory indices were re-assessed after challenge with terbutaline 1.5 mg by inhalation. The three beta-blocking agents caused equal falls in exercise heart rate two hours after ingestion, indicating the equipotency of the cardiac effects. The three agents reduced significantly and to the same extent FEV and PEFR both before and after exercise. The respiratory indices clearly improved after stimulation with terbutaline. The response to terbutaline was less marked after acebutolol, which may indicate that it has a lower degree of beta-selectivity. The beta-blockers did not show any influence on bronchodilatation during exercise, or on exercise-induced bronchospasm. [ABSTRACT FROM AUTHOR]

The effects or oral atenolol (100 mg once/day) and metoprolol (100 mg once/day, 100 mg twice/day and 300 mg once/day) have been compared with placebo on the heart rate and systolic blood pressure responses to exercise in 5 healthy volunteers. The drugs were given for 5 days in a double blind randomised fashion with each volunteer receiving each dose of drug. Measurements were made after the first dose on day 1 and after 5 days of dosing. The results on both heart rate and systolic blood pressure showed that overall (over a 24 h period) after acute (day 1) or after chronic (5 days) dosing, atenolol 100 mg once/day, metoprolol 100 mg twice/day and 300 mg once/day, were equivalent as β-adrenoceptor blocking doses. Thus milligram for milligram atenolol and metoprolol do not produce equivalent blockade on the cardiovascular system of man. [ABSTRACT FROM AUTHOR]

In 12 normal volunteers the interaction between the metabolic and cardiovascular effects of adrenaline and either a cardioselective (atenolol 150 mg p. o. for 1 week) or a non-selective β-blocker with intrinsic sympathomimetic activity (pindolol 15 mg p. o. for 1 week) were studied. Equiactive doses of the β-blockers were investigated with respect to their metabolic effects. There were profound differences in the metabolic profile of the two substances: the non-cardioselective beta-blocker caused significant inhibition of the lipolytic, glycogenolytic and the growth hormone-releasing effects of adrenaline when compared to the cardioselective agent. The results indicate that, during non-cardioselective beta-blockade, metabolic effects occur which should favourably influence myocardial oxygen consumption by making myocardial performance more economical. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of atenolol were determined following acute intravenous and chronic oral administration to 20 subjects with a glomerular filtration rate (GFR) between 5 and 113 ml/min. Plasma levels in a further 5 patients on haemodialysis were measured after intravenous treatment. The mean half life of elimination increased from 5.9 h in patients with normal renal function to 42.1 h in preuraemic patients (GFR <10 ml/min) following a single i. v. dose. The half life of elimination following chronic oral administration was not significantly different. Mean peak plasma concentrations increased from 540 ng/ml in patients with normal renal function to 1493 ng/ml in preuraemic patients following chronic oral treatment with 100 mg/day. The mean half life of elimination during a single haemodialysis treatment was 4.3 h. In patients with a GFR >30 ml/min the normal daily dose of atenolol should be employed, in patients with a GFR between 10 and 30 ml/min the dose should be reduced by half, and in patients with a GFR <10 ml/min a reduction by three quarters of the normal dose is recommended. [ABSTRACT FROM AUTHOR]

To show whether repeated administration of atenolol for several days would influence its pharmacokinetic parameters and the extent and duration of the pharmacologic responses, the plasma level of atenolol and changes in heart rate, blood pressure and plasma renin activity were measured in 12 hypertensive patients at various times of day (9 a. m., 12 noon, 3 p. m. and 7 p. m.) after oral administration of the first dose of atenolol 100 mg, again during the 7th and 14th days of continued once-daily administration of the same dose, and finally during the three days following withdrawal of the drug. The peak plasma concentration of atenolol (about 600 ng/ml) was found 3 h after administration of the first dose, and measurable amounts (50-70 ng/ml) were found after 24 h. None of the pharmacokinetic characteristics were changed by administration of a single daily dose for two weeks. After withdrawal of the drug, detectable amounts of atenolol were found in plasma for at least 48 h. The first dose of atenolol caused prompt (3 h) and prolonged (up to 24 h) lowering of supine and standing systolic and diastolic blood pressures, slowing of supine and standing heart rate, reduction of the blood pressure and heart rate responses to dynamic exercise, and a decrease in plasma renin activity. The extent and time-course of all these responses were not influenced by repeated once-daily administration of the 100 mg dose for two weeks. Most of the effects continued during the withdrawal days, the lowering of blood pressure being somewhat more prolonged than the slowing of heart rate. It is concluded that a once-daily dose of atenolol 100 mg decreases blood pressure and heart rate throughout the following 24 h, without excessive daily fluctuation in its effects, and without signs of tolerance or accumulation. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of atenolol with and without the co-administration of chlorthalidone were studied in five hypertensive subjects. Concomitant administration of chlorthalidone appears to have little if any effect on the pharmacokinetics of atenolol during treatment for 7 days. The atenolol elimination half-lives were 6.7±1.1 and 6.3±0.9 h, respectively, with and without chlorthalidone. Two healthy volunteers also received a single 50 mg oral dose of chlorthalidone. Their blood profiles and pharmacokinetics were similar to those observed in hypertensive subjects, but a statistically significant difference (p<0.01) was found between the urinary excretion half-lives of chlorthalidone. This difference may be because chronic administration of the drug caused saturation of red cell binding. [ABSTRACT FROM AUTHOR]

The influence of food intake on the bioavailability of the beta-adrenoceptor blocker atenolol was assessed by measurement of its single-dose kinetics in ten healthy volunteers, who took 100 mg both in the fasting state and together with a standardized breakfast. Food intake significantly shortened the time to reach peak concentration (2.7 h vs 1.5 h), but caused a significant reduction in AUC values, the mean decrease being 20%. The elimination half-life was unaffected. Atenolol, which is relatively hydrophilic, is incompletely absorbed in the fasting state, and escapes first-pass metabolism. The present findings indicate that food intake causes further impairment of its absorption, even though the absorption rate may initially be enhanced. This contrasts with previous observations on the more lipophilic beta-adrenoceptor blockers propranolol and metoprolol. [ABSTRACT FROM AUTHOR]

The acute effects upon blood pressure and sympathetic outflow of two beta adrenoceptor blocking drugs, propranolol and atenolol, are described in five healthy normotensive subjects. Supine blood pressure, heart rate, plasma noradrenaline, and urinary catecholamine excretion were measured before and at intervals for 24 h after a single oral dose of either propranolol 200 mg, atenolol 100 mg, or placebo. Propranolol caused a fall in blood pressure and heart rate of 17.2/14.1 mm Hg and 20.4 beats/min respectively two hours after dose. Atenolol caused a fall in blood pressure of 11.4/18.6 mm Hg withih 7 h of the dose, and a fall in heart rate of 13.8 beats/min after 2 h. The reduction in blood pressure after single high dose beta adrenoceptor blockade is established. The synchronous reduction in blood pressure and heart rate after propranolol was not associated with an increase in peripheral sympathetic activity as assessed by the biochemical indices. It is conceivable that the reduction in blood pressure during beta adrenoceptor blockade may be due in part to inappropriately low sympathetic activity but this cannot be the main mechanism of pressure reduction. [ABSTRACT FROM AUTHOR]

The non-stimulant cardioselective beta adrenocepter antagonist atenolol has been studied in volunteers in order to define its pharmacokinetic characteristics. Atenolol (100 and 200 mg orally) is rapidly absorbed, reductions in heart rate and systolic pressure being observed in 30 min. The effect persists for up to 8 h. Over 85% of an intravenous dose is excreted in urine within 24 h but only 50% of an oral dose. The bioavailability of approximately 50% is due to reduced absorption. Peak blood levels are observed at 2-4 h and the half life of atenolol given orally is 5-6 h. Atenolol reduces the cardiac response to standing and head-up tilt. It does not reduce circulating levels of renin but slightly impairs the renin response to tilt. Atenolol both orally and intravenously reduces supine diastolic pressure about four hours after administration, the effect persisting for up to 24 h. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of atenolol, a new cardioselective β-adrenoceptor blocking agent, were determined following both acute and chronic dosing in 33 hypertensive patients with widely differing levels of renal impairment. In patients with normal renal function the atenolol half-life was calculated to be about six hours following single 100 mg oral doses. This value increased markedly in patients with renal insufficiency and the blood clearance of atenolol was found to have a significant correlation with the glomerular filtration rate. This demonstrated the importance of the kidneys in the elimination of the drug. After 8 weeks oral treatment with atenolol (100 mg twice daily) a significant decrease in blood pressure, heart rate and plasma renin activity was observed, but no correlation was established between the blood levels of atenolol and any of its pharmacodynamic effects. A positive correlation was found however between the anti-hypertensive action of atenolol and the pretreatment value of the plasma renin activity. [ABSTRACT FROM AUTHOR]

The bronchial effect of intravenous atenolol (ICI 66.082) has been studied in a doubleblind cross over trial in 10 patients with pronounced, labile bronchial asthma. A single i. v. dose of atenolol 3 mg, sufficient to cause a fall in heart rate and systolic blood pressure at rest, induced only a slight and clinically almost negligible impairment of ventilatory function. An ordinary therapeutic dose of salbutamol by inhalation far outweighed the bronchial effect of atenolol. The drug appears promising with regard to its cardio-selective properties. [ABSTRACT FROM AUTHOR]

The comparative potency of two beta-blockers, propranolol and atenolol, in the inhibition of exercise tachycardia and isoproterenol-tachycardia has been studied in two groups of hypertensive patients, using oral doses which were increased weekly. A linear correlation was observed between the reduction in exercise tachycardia and the dose of each drug, up to a daily dose of propranolol 480 mg and atenolol 600 mg. Propranolol was slightly (0.7/1) more potent in decreasing maximal exercise tachycardia than atenolol when tested in low doses (below 100 mg); at higher doses (480 mg) no differences were found. However, atenolol was 10 times less potent than propranolol in blocking isoprenaline-induced tachycardia, which seems to be related to the cardioselectivity of atenolol. [ABSTRACT FROM AUTHOR]

Propranolol was given to 30 patients with essential hypertension following randomised, double-blind administration of either placebo or a new cardioselective beta-adrenergic receptor antagonist, atenolol (Tenormin, ICI 66 082). Both atenolol and propranolol caused statistically significant reduction of recumbent and erect blood pressure and heart rate. There were no important differences between these variables on comparison of atenolol and propranolol. [ABSTRACT FROM AUTHOR]

Objective: To study the influence of the lipase inhibitor orlistat on the pharmacokinetics of the antihypertensive drugs atenolol, furosemide, captopril and nifedipine. Methods: Four open-label, crossover studies were performed on six to eight healthy male volunteers. Orlistat was given in doses of 50 mg 3 times daily mid-meal for 7 (nifedipine and captopril) or 8 days (atenolol and furosemide). The four antihypertensive drugs (atenolol 100-mg tablet, furosemide 40-mg tablet, captopril 50-mg tablet and nifedipine 20-mg slow-release tablet) were administered in single doses twice, once before and once together, with orlistat at the end of the orlistat treatment period. Results: The plasma concentration time profiles and the pharmacokinetic parameters estimated for these drugs were in the expected range, except for furosemide, whose bioavailability was lower than reported in the literature. This was probably due to the fact that furosemide was given during a meal. There were minor, but statistically significant, differences in one of the pharmacokinetic parameters of furosemide and nifedipine (no difference for captopril and atenolol) when these drugs were given alone and in combination with orlistat: the half-life of furosemide was slightly longer, the time to peak plasma concentrations of nifedipine was slightly longer. None of these are considered to be clinically significant changes. Conclusions: The lipase inhibitor orlistat given 50 mg 3 times daily does not alter the pharmacokinetics of atenolol, furosemide, nifedipine and captopril to a clinically significant extent. [ABSTRACT FROM AUTHOR]

Physical exercise causes transient albuminuria. The mechanisms of postexercise albuminuria are not fully clarified but stimulation of the reninangiotensin system (RAS) probably plays a major role through intrarenal haemodynamic changes causing an elevated filtration pressure. In a randomised, double-blind, crossover study we compared the effects on urinary albumin excretion (UAE) of lisinopril (L) and atenolol (A) therapy, i.e. we aimed to investigate whether inhibition of the RAS or inhibition of β-adrenoceptor-mediated effects of the sympathetic nervous system differed with regard to changes in UAE. Sixteen patients with uncomplicated primary hypertension were studied. Four standardised bicycle ergometer exercise tests were performed, before and after each active treatment period. UAE 30 min postexercise, determined by radioimmunoassay, was significantly lowered by both treatments: -278 μg·min (L) and-199 μg·min (A). The reduction of postexercise UAE achieved by treatment with the angiotensin-converting enzyme (ACE) inhibitor (L) was significantly greater than that achieved by the β-selective adrenoceptor blocker treatment. Blood pressure (BP) at rest and during exercise were equally reduced by both drugs. In conclusion, this study showed that antihypertensive treatment with an ACE inhibitor was more effective in reducing exercise-induced albuminuria than a β-selective adrenoceptor-blocking agent with a similar degree of BP reduction in patients with uncomplicated primary hypertension. This suggests that the RAS plays a major role in postexercise albuminuria in hypertensive subjects. The clinical significance of this finding, however, remains to be clarified. [ABSTRACT FROM AUTHOR]

The aim of the present study was to evaluate the central effects of single doses of the β-adrenoceptor antagonist atenolol and the calcium antagonist nifedipine retard, alone and in combination, in normal subjects. Twelve normal males received single oral doses of atenolol 100 mg, nifedipine retard 20 mg, atenolol 100 mg and nifedipine retard 20 mg in combination, diazepam 5 mg (active control), and each of two matching placebos in a double-blind, randomised fashion. Psychomotor performance was assessed using digit symbol substitution, letter cancellation (LCT), continuous attention, choice reaction time, finger tapping, immediate recall and short-term memory. Two flash fusion and critical flicker fusion thresholds were measured and subjective assessments made using visual analogue scales (VAS). Diazepam 5 mg significantly worsened LCT scores at 4h, significantly impaired alertness at 2 h and 4 h, and tended to increase reaction time and impair continuous attention and physiological measurements. Atenolol 100 mg alone significantly reduced alertness at 2 h and 4 h, and also tended to impair physiological measurements. Nifedipine retard 20 mg produced no significant psychomotor effects. Combined atenolol and nifedipine retard administration produced a small but significant improvement in continuous attention and a reduction in body sway, with no adverse effects being evident on performance or subjective awareness. The results suggest that no significant adverse effects on psychomotor performance are produced by single doses of atenolol 100 mg and nifedipine retard 20 mg when given together in normal subjects. The combination may therefore be useful in the treatment of hypertensive patients requiring dual therapy, and in whom adverse central effects are of particular importance. [ABSTRACT FROM AUTHOR]

Fifty patients with mild to moderate essential hypertension were randomized to receive either 20 mg fosinopril daily for 16 weeks or placebo for 4 weeks followed by 12 weeks of 50 mg atenolol daily. Prior to these 16 weeks there was a placebo wash-out period of 2-6 weeks. Blood pressure measurements, euglycaemic, hyperinsulinaemic glucose clamps, and intravenous glucose tolerance tests (IVGTT) were performed at baseline and after 4 and 16 weeks. Blood lipid status was evaluated at baseline and 16 weeks. The insulin sensitivity index (M/I) increased by 12% during the prolonged placebo period, and subsequently decreased by 12% during treatment with atenolol in that group. A post-hoc analysis of covariance indicated that the increase in insulin sensitivity during the initial 4 weeks may have been due to carry over effects from previous anti-hypertensive treatment. Fosinopril increased glucose disappearance during IVGTT at 4 and 16 weeks ( k values 1.46 and 1.33 vs 1.10 at baseline) but had no effect on insulin sensitivity. The change in insulin sensitivity and serum triglycerides during treatment with fosinopril was related to angiotensin-converting enzyme inhibition in serum. In conclusion, carry-over effects from previous anti-hypertensive medication were indicated in this study, probably because of an insufficient wash-out period in many patients. Therefore, 4 weeks of placebo wash-out in all patients is advisable in this kind of investigation. [ABSTRACT FROM AUTHOR]

The central effects of atenolol (50 mg tds) and captopril (50 mg tds) ingested for a period of seven days were studied in ten healthy volunteers. A placebo and two active control drugs, methyldopa (250 mg tds) and oxazepam (10 mg), were included in the design. Oxazepam was ingested on the seventh day only, with a placebo being taken on the preceding six days. On the seventh day, central effects of the drugs were tested at 10.00-11.00 h (session 1), immediately before the subjects' last dose of each drug and at 2.5-3.5 h after the final dose of each drug (1330-1430 h, session 2). Performance was assessed using digit symbol substitution, continuous attention, letter cancellation, choice reaction time, finger tapping, immediate and short-term memory, critical flicker fusion and two flash fusion. Subjects assessed their mood and well-being on a series of 12 visual analogue scales. Recordings of the EEG and body sway were carried out. Neither atenolol nor captopril altered performance at any of the skills tested. There were no effects on subjectively assessed alertness or mood with captopril, while atenolol significantly increased wakefulness in session 2 and when the two sessions were meaned. Similarly, captopril did not modify body sway, while with atenolol there was a significant decrease in activity in the frequency range 1.0-2.75 Hz from session 1 to session 2. Both captopril and atenolol modified the electrical activity of the brain, with captopril increasing delta and theta activity and atenolol reducing delta, alpha and beta activity. Methyldopa significantly increased the number of involuntary rest pauses in the finger tapping task, and the choice reaction time from session 1 to session 2. There was a decrease in passivity during the first session and an increase in wakefulness in session 2 with methyldopa. This drug also decreased body sway in the frequency range 1.0-2.75 Hz activity in session 2, while oxazepam decreased bodys was at 1.0 to 2.75 Hz and increased activity at 2.5-3.0 Hz in session 2. Oxazepam reduced delta, theta and alpha content of the EEG. The present study has been unable to demonstrate any development of adverse central effects with captopril over a period of 7 days of drug ingestion. With atenolol adverse effects were present following short term dosing but were not more pronounced than with acute ingestion seen in previous studies. However effects on the electrical activity of the brain with atenolol remained after 7 days suggesting that the changes reported previously with single ingestions do not disappear. [ABSTRACT FROM AUTHOR]

Twelve normal male subjects received single oral doses of atenolol 100 mg (AT), bendrofluazide 5 mg (BFZ), combined atenolol 100 mg and bendrofluazide 5 mg (AT/BFZ), diazepam 5 mg (Dz), or one of two matching placebos, on each of 6 study days. Tests of psychomotor performance [digit symbol substitution (DSST), letter cancellation (LCT), continuous attention, choice reaction time (CRT), finger tapping, short-term memory, body sway], physiological measurements [critical flicker fusion (CFF), two-flash fusion (2FF)] and subjective assessments using visual analogue scales (VAS), were performed at 2 and 4 hours post-ingestion. Dz (active control) significantly worsened VAS scores at 2 h (+0.68) and reduced DSST scores at both 2 h (−15.0) and 4 h (−11.0). AT and BFZ given alone, each produced significant worsening of VAS at 2 h [AT +1.0; BFZ +1.38], but had no significant effects on performance. In combination however, AT/BFZ at 4 h produced significant impairment of DSST scores (−10.4), reduced finger tapping (−16.5) and increased involuntary rest pauses (+16.5). Despite these effects, no change in VAS scores occurred. In summary, we have demonstrated significant impairment of psychomotor performance in normal subjects with the AT/BFZ combination, which was not evident with the single agents and which occurred in the absence of a change in subjective awareness. These central effects may have important clinical implications for patients taking combined antihypertensive medication. [ABSTRACT FROM AUTHOR]

Dihydropyridine calcium antagonists are established second line treatment for angina uncontrolled by β-adrenergic blockers. Amlodipine is a recently introduced, dihydropyridine with a long half life. In a double blind, placebo controlled, cross over trial we assessed the efficacy and safety of amlodipine in 20 patients with persistent angina despite treatment with atenolol. 17 male patients (mean age 58 y) completed the study. Two patients were withdrawn during placebo because of worsening angina and one withdrew whilst on amlodipine because of palpitations. Compared with baseline, amlodipine prolonged exercise time to S-T segment depression by a median of 12.5%; significantly more than was found with placebo (median 0%). The improvement in exercise time and time to angina also tended to be greater for amlodipine than placebo. GTN consumption, at a median of 1.3/week, was significantly less with amlodipine than placebo (2.8). Attacks of angina were also reduced. Standing systolic and diastolic blood pressures and sitting systolic blood pressure were lower with amlodipine than placebo. Heart rate did not change. There was no change in cardiac output (measured by doppler aortovelography) when amlodipine was added to atenolol. Holter monitor measurements of 24 h maximum and minimum heart rate, heart rate variation and extrasystole counts were the same for amlodipine and placebo. In conclusion, amlodipine is effective in patients with angina inadequately controlled by atenolol alone, and does not interfer with cardiac rhythm or function. [ABSTRACT FROM AUTHOR]

A randomised crossover study has been done to compare the antihypertensive efficacy of enalapril and atenolol in 45 smoking, hypertensive men. Treatment was started with enalapril 20 mg/d or atenolol 50 mg/d and, if necessary, the doses were doubled after 4 weeks to achieve a sitting diastolic blood pressure ≤ 95 mm Hg, after which hydrochlorothiazide was added, if necessary. Both drugs lowered blood pressure significantly. However, enalapril was more efficient in lowering both systolic and diastolic blood pressure; the mean difference was significant after both 4 and 8 weeks in the sitting systolic (11.6 mm Hg and 7.9 mm Hg) and diastolic (3.3 mm Hg and 3.0 mm Hg) pressures and in the erect systolic pressures (8.2 mm Hg and 7.2 mm Hg), and after 8 weeks in the supine systolic pressure, too (8.9 mm Hg). The effect on enalapril was especially marked in moderate (<20 cigarettes/day) smokers. The need for diuretics was also significantly less in the enalapril group. It appears that angiotensin-converting enzyme inhibitors may be superior to β-adrenoceptor blockers in the treatment of hypertensive smoking patients. [ABSTRACT FROM AUTHOR]

The presence of slightly increased urinary albumin excretion (UAE), even at levels well below levels detectable by an ordinary dipstick, has been suggested as a predictor of cardiovascular morbidity and as a reflection of the degree of overall vascular permeability. The aim of the present investigation was to study the effects of two different antihypertensive drug regimens, an ACE inhibitor and a β-adrenoceptor antagonist, on the low UAE rate observed in subjects with uncomplicated, mild to moderate primary hypertension. After a 4-week placebo run-in period, 49 patients (mean age 54 y) were randomly assigned in a double blind manner either to further 4 weeks on placebo (P, n =15), 8 weeks on lisinopril (L, n = 17; 20 mg/40 mg o. d.) or 8 weeks on atenolol (A, n =17; 50 mg/100 mg o. d.). The 24-h UAE was measured every second week. At entry and after 4 weeks the glomerular filtration rate and the renal plasma flow were measured. Both drugs lowered blood pressure (BP) to a similar extent after 4 and 8 weeks of treatment; the blood pressures were 160/106 (P), 159/104 (L) and 154/103 (A) at entry, and 133/83 (L) and 134/87 (A) at the end of the study after 8 weeks. On entry the 24-h UAE in all patients ranged from 4 to 49 mg (mean 14.1 mg), and it did not differ significantly between groups. After 4 weeks the UAE during 24 h was reduced by approximately one third in the lisinopril-treated group, and by 10 % in the atenolol reated group, whereas it remained unaltered in the group on placebo. After 8 weeks the 24-hour UAE was approximately 20 % lower compared to baseline levels in the lisinopril-treated patients. In the atenolol-treated group the UAE was unaltered compared to baseline. However, none of the changes in the UAE was statistically significant, nor were there any statistically significant differences between the two antihypertensive regimens. Moreover, there were no significant effect of the lisinopril or atenolol treatment on renal function or on renal haemodynamics. It is concluded that in patients with uncomplicated, mild to moderate hypertension both an ACE-inhibitor, such as lisinopril, as well as a β-selective adrenoceptor blocking agent, such as ate [ABSTRACT FROM AUTHOR]

Haemodynamic changes in the carotid and brachial arteries produced by single doses of four antihypertensive drugs (nicardipine, enalapril, atenolol, and urapidil) have been studied in 12 patients with essential hypertension. Measurements were performed noninvasively using a mechanographic method and B-mode pulsed Doppler ultrasonography. Within 7 h all of the drugs had caused a significant reduction in blood pressure, whereas heart rate showed a significant change only after atenolol. All the drugs produced a marked reduction in brachial pulse-wave velocity. Only nicardipine caused a significant reduction in vessel wall tension both in the carotid and brachial arteries, while brachial peripheral resistance was significantly reduced by all the drugs except atenolol. Neither atenolol nor enalapril caused any significant reduction in carotid peripheral resistance. The results show that all four antihypertensive drugs led to a beneficial increase in arterial compliance despite their different effects on peripheral resistance. [ABSTRACT FROM AUTHOR]

In a study in mild hypertensives, the impact of mental and physical stress on plasma epinephrine (E), norepinephrine (NE), and on their ratio (NE/E) was evaluated. The effect of two β-adrenoceptor blocking drugs, atenolol and bopindolol, on plasma catecholamine levels was also examined. Each stressful stimulus significantly increased the NE and E levels compared to rest. The increase was progressive from mental stress, through the handgrip test to the treadmill test. A slight decrease in the NE/E ratio was observed following mental stress and the handgrip test, while this ratio increased during the treadmill test. No significant impact of beta blocking treatment on catecholamine levels was observed under any test condition. [ABSTRACT FROM AUTHOR]

We have evaluated Sramek's method of impedance cardiography as a non-invasive way of detecting the cardiovascular effects of drugs. We made cardiovascular measurements using the method during passive tilting and exercise 2 h after the oral administration of atenolol (50 and 100 mg), propranolol (40 and 80 mg), pindolol (5 and 10 mg), and placebo in seven separate studies involving eight healthy male volunteers. Equivalent doses of the pure antagonists atenolol (β) and propranolol (β, β) produced similar reductions in heart rate, systolic blood pressure, and cardiac index, and increases in stroke volume and total peripheral resistance, particularly during exercise. In contrast the partial agonist pindolol produced increases in heart rate and cardiac index, and reductions in peripheral resistance at rest. During passive tilting and exercise pindolol reduced heart rate, but cardiac output and total peripheral resistance were unchanged except at the highest levels of exercise. The similar cardiovascular effects of atenolol and propranolol, but differing effects of pindolol, are consistent with reports using other methods of measurement. This suggests that impedance cardiography may have a place in the non-invasive assessment of the cardiovascular effects of drugs. [ABSTRACT FROM AUTHOR]

A placebo controlled double blind crossover study was performed in 12 healthy volunteers to compare the cardiovascular effects of single oral doses of nifedipine (5, 10 and 15 mg) and nicardipine (20 and 30 mg) in the presence of atenolol 100 mg. Haemodynamic measurements were made by transthoracic electrical bioimpedance cardiography (TEBC) 2 h following drug administration during passive tilting, graded bicycle exercise (30-150 W), and recovery from exercise. In the absence of calcium channel blockade, atenolol reduced mean blood pressure, heart rate, and cardiac index, and increased stroke volume, peripheral resistance, pre-ejection period, and ventricular ejection time, particularly during and after exercise. In comparison with atenolol alone, addition of nifedipine or nicardipine reduced peripheral resistance but did not produce significant changes in stroke volume, cardiac output, dZ/dt[max], pre-ejection period (PEP), Ventricular ejection time (VET), PEP/VET, or Heather index at any point in the experiment. Similar reductions in peripheral resistance were produced by nifedipine 10 mg and nicardipine 20 and 30 mg. These apparently equivalent doses of nifedipine and nicardipine had similar effects on stroke volume, cardiac index, PEP/VET and Heather index. Thus the increases in ventricular performance previously demonstrated in association with nifedipine and nicardipine therapy were not observed in the presence of β-adrenoceptor blockade. Under these conditions no important differences have been observed in the cardiovascular effects of these two calcium channel blockers. [ABSTRACT FROM AUTHOR]

The influence of clinical doses of drugs that affect β-adrenoceptors has been examined on heart rate, blood pressure, duration of exercise, and on electrolyte concentrations (Na, K, Ca and Mg) during recovery from exercise in healthy volunteers. The drugs used were a β-adrenoceptor antagonist atenolol, a nonselective β-adrenoceptor antagonist propranolol, and a cardioselective, partial β-adrenoceptor agonist with 43% ISA activity, xamoterol. The duration of exercise was smaller on propranolol. Maximum exercise heart rate and blood pressure were reduced significantly by propranolol and atenolol. Xamoterol reduced maximum exercise heart rate and had no effect on blood pressure. The degree of breathlessness and fatigue revealed no differences between treatments. Recent evidence has suggested an association between hyperkalaemia and hypomagnesaemia with an increase in the occurrence of arrythmias following acute myocardial infarction. Exercise-induced hyperkalaemia has been suggested as a factor in sudden death. The results confirmed a rise in serum potassium during exercise and attenuation of the fall during recovery under β-adrenoceptor blockade. Xamoterol was no different from placebo in these respects. Exercise also produced a rise in magnesium levels and during recovery the level fell below baseline. Both these effects were attenuated by propranolol. Calcium levels were not affected by any of the treatments. [ABSTRACT FROM AUTHOR]

Six normal subjects were given once daily treatment for 15 days with placebo (PL), betaxolol 10 mg (B10), 40 mg (B40); atenolol 100 mg (A100); and nadolol 40 mg (N40). Measurements of β-adrenoceptorblockade (reduction of exercise heart rate) and of β-adrenoceptor-blockade (attenuation of isoprenaline induced finger tremor) were made after the first, eighth and fifteenth doses of each drug. Plasma concentrations showed dose related increases between 10 mg and 40 mg doses of betaxolol, and there was significant drug accumulation at steady state compared with after single dosing. The reduction in exercise heart rate (EHR) with B10 was less in comparison with all other treatments. There were no significant differences in effects between single and chronic-dosing for any of the treatments (% reduction EHR compared with placebo, on days 1 and 15): B10 (18.2, 19.0), B40 (28.6, 26.5); A100 (22.7, 23.1); N40 (26.6, 23.8). Dose-ratios for attenuation of isoprenaline-induced finger tremor (IT) were significantly greater with B40 compared with B10 or A100 (no dose-ratio for finger tremor could be calculated for N40). There were no differences between single and chronic-dosing (IT dose-ratios on days 1 and 15): B10 (3.0, 2.5), B40 (4.4, 5.3); A100 (3.0, 3.0). The attenuation of isoprenaline-induced chronotropic response (IH) by N40 was significantly greater in comparison with all other treatments. IH dose-ratios (on days 1 and 15) were as follows: B10 (2.8, 3.6), B40 (5.1, 5.8); A100 (3.6, 3.6); N40 (19.0, 17.4). Thus, despite drug accumulation after chronic-dosing, there was no evidence of any increase in either β or β-adrenoceptor antagonism at steady-state in comparison with after single-dosing. The apparent dissociation between plasma concentration and β-adrenoceptor antagonism after chronic-dosing my be a consequence of β-adrenoceptor up-regulation, resulting in partial attenuation of β-blockade. [ABSTRACT FROM AUTHOR]

Disturbances in the fibrinolytic system have been associated with cardiovascular disease and its risk factors. In the present study the effects of an alpha-adrenoceptor inhibitor (doxazosin) and a selective beta-adrenoceptor blocker (atenolol) on the fibrinolytic system have been evaluated. Eighty four subjects with previously untreated mild to moderate hypertension and elevated serum cholesterol were randomized to receive atenolol or doxazosin in a double-blind study over 6 months. Tissue plasminogen activator(tPA) and plasminogen activator inhibitor (PAI-1) were measured in citrated plasma samples before and after venous occlusion before and at the end of the study period. tPA activity after venous occlusion and tPA capacity were significantly increased after doxazosin as compared to pretreatment values. The fibrinolytic variables did not change in the atenolol group. Thus, doxazosin but not atenolol, improved the activity of the fibrinolytic system in patients with hypertension and an elevated serum cholesterol level. This effect of doxazosin warrants consideration when selecting a first-line antihypertensive drug. [ABSTRACT FROM AUTHOR]

A dose-ranging study was performed to compare the β-adrenoceptor selectivity of bisoprolol with that of atenolol and nadolol. Seven normal subjects (mean age 26 y) were given single oral doses of bisoprolol 5 mg (B5), 10 mg (B10), 20 mg (B20); atenolol 50 mg (A50), 100 mg (A100); nadolol 40 mg (N40); and placebo (PL), in a single blind randomised cross-over design. β-adrenoceptor responses were assessed by attenuation of finger tremor and cardiovascular responses to graded isoprenaline infusions. Dose-response curves were constructed, and doses of isoprenaline required to increase finger tremor by 100% (IT), heart rate by 25 beats/min (IH), SBP by 25 mm Hg (IS), cardiac output by 35% (IC), and decrease DBP by 10 mm Hg (ID), after each treatment were calculated. These indices were compared with placebo response and expressed as dose-ratios. Exercise heart rate (EHR) was used to assess β-adrenoceptor blockade. There were dose-related increases in plasma concentrations of bisoprolol and atenolol. Reduction of EHR was significantly less with B5 (16.8%) in comparison with all other treatments: B10 21.9%, B20 23.1%; A50 22.5%, A100 22.6%; N40 22.9%. There were small but significant reductions in isoprenaline-induced tachycardia with bisoprolol and atenolol, although mean dose-ratios were considerably less in comparison with N40 (IH dose-ratios): B5 2.55, B10 3.18, B20 3.93, A50 2.91, A100 4.89, N40 17.23. There were similar patterns for the other isoprenaline responses. These results show that conventional doses of bisoprolol (10 mg) and atenolol (50 mg) produced equal antagonism of β and β-adrenoceptors, and therefore possess equal degrees of β-adrenoceptor selectivity. Increasing doses of bisoprolol and atenolol were associated with partial loss of selective β-adrenoceptor blockade, although antagonism of β-adrenoceptors was significantly less compared with the effects of nadolol. [ABSTRACT FROM AUTHOR]

In a double-blind, randomised, cross-over study, the pharmacokinetic/dynamic effects and subjective symptoms of a new controlled-release (CR) formulation of metoprolol (50 and 100 mg) have been compared with atenolol (50 mg) and placebo in 20 elderly healthy subjects. The metoprolol CR formulation displayed an even plasma concentration-time profile over the dosage interval while atenolol produced a peak at 2-4 h. All three active treatments produced significant β-blockade at 24 h compared to placebo. Four hours after dose intake, the degree of β-blockade was significantly greater with conventional atenolol 50 mg than with either dose of metoprolol CR. Subjective well-being was examined with a self-administered questionnaire (MSE-profile), including three dimensions: Contentment, Vitality and Sleep. No significant differences were detected between placebo and either dose of metoprolol CR. At 2 h, following atenolol, a deterioration in Vitality was observed compared to placebo and metoprolol CR 100 mg. At the end of the dosage interval there was no longer any significant difference between the treatments. Perceived leg fatigue during exercise, evaluated 4 h after dosing, was more pronounced during treatment with atenolol than metoprolol CR 50 mg. The results suggest that the metoprolol CR formulation was not associated with significant effects on subjective well-being, whereas atenolol caused a deterioration at the time of the peak plasma concentration of the drug. [ABSTRACT FROM AUTHOR]

The effects of single oral doses of the angiotensin converting enzyme (ACE) inhibitor quinapril (CI-906) 40 mg and the cardioselective β-adrenoceptor blocker atenolol 100 mg on sympathetic and parasympathetic function and on exercise capacity have been studied in 8 healthy young men. The trial followed a double-blind, placebo controlled, randomized cross-over design, with at least one week between treatments. Blood pressure (BP) and heart rate (HR) at rest were slightly reduced by atenolol but were not affected by quinapril. Atenolol impaired the sympathetically mediated increases in HR and BP caused by standing, immersion of the hand into melting ice, the Valsalva manoeuvre and isometric forearm exercise. Quinapril did not influence those responses nor the vagally mediated bradycardia of the diving reflex. Atenolol, however, augmented the vagal bradycardia, presumably by sympathetic inhibition. In a dynamic bicycle ergometer test with a stepwise increasing work load, exercise performance was decreased by atenolol but not by quinapril. Inhibition of the renin-angiotensin system by quinapril was shown by a marked decrease in serum ACE activity and a several-fold increase in plasma renin activity (PRA). Atenolol produced a moderate reduction in PRA. Before or during exercise, plasma noradrenaline and adrenaline were not influenced by either drug. The results indicate that, unlike the atenolol-induced β-adrenoceptor blockade, ACE inhibition by a single dose of quinapril had no clear effect on autonomic nervous function or exercise capacity. [ABSTRACT FROM AUTHOR]

The effect of a non selective and a cardio-selective beta-blocker on basal and exercise-stimulated plasma atrial natriuretic peptide concentrations in healthy volunteers has been studied. Nine healthy volunteers received single oral doses of 5 mg tertatolol, 100 mg atenolol or placebo, at one week intervals, in a double blind cross over trial. At rest plasma atrial natriuretic peptide, aldosterone, antidiuretic hormone and cyclic GMP concentrations and plasma renin activity were not modified by the treatments. During exercise plasma atrial natriuretic peptide concentrations were significantly increased by each treatment, the increment being significantly greater on beta-blockers than on placebo. The rise in atrial natriuretic peptide was 72% after placebo (from 24 to 42 pg/ml), 184% after atenolol (from 30 to 86 pg/ml), and 183% after tertatolol (from 34 to 95 pg/ml), respectively. Thus, the study has shown that in healthy subjects the plasma natriuretic peptide concentration is increased by exercise and that the increase is considerably and equally potentiated by selective and non selective beta-adrenoceptor blockade. The effect may be mainly due to a reduction in ventricular contractility with an increase in atrial pressure. The beta-blockers did not influence the resting plasma atrial natriuretic peptide levels, which suggests that in healthy subjects basal atrial natriuretic peptide secretion is not controlled via beta-receptors. [ABSTRACT FROM AUTHOR]

We have compared the efficacy and pharmacokinetics of bisoprolol, a new cardioselective beta-adrenoceptor antagonist, with atenolol in a randomized double-blind crossover study in 12 patients (mean age 53.5 y) with mild to moderate essential hypertension. After a two week placebo wash-out period without any antihypertensive therapy, the patients were given bisoprolol 10 mg daily or atenolol 50 mg daily, increasing to 20 mg or 100 mg respectively if the sitting diastolic blood pressure did not fall below 90 mm Hg after two weeks of therapy. Crossover occurred after six weeks of active therapy followed by two weeks of placebo wash-out. After 6 weeks of therapy both drugs significantly reduced sitting and standing diastolic blood pressures (bisoprolol by 15% and 16% respectively, atenolo by 11% in both cases). However, while sitting and standing systolic pressures were significantly reduced by bisoprolol (13% and 16% respectively), only standing systolic pressures were significantly reduced by atenolol (11%), and this reduction was significantly less than with bisoprolol ( p<0.05). Both drugs similarly reduced mean sitting and standing heart rates. There were no significant differences between the single-dose and steady-state kinetics of either bisoprolol or atenolol. The mean plasma elimination half-life (t) increased from 12.9 to 13.2 h during steady state on bisoprolol and from 7.2 to 11.5 h on atenolol. The apparent volume of distribution (V) was greater for bisoprolol than for atenolol after single dosing (235 1 vs 146 1) and at steady state (216 1 vs 137 1), but clearances were similar for both drugs. The maximum plasma concentration (C) of bisoprolol increased from 45 μg·l to 72 μg·l during steady state and the C of atenolol increased from 321 μg·l to 410 μg·l Adverse effects occurred in only one patient (lethargy while taking atenolol). These results suggest that bisoprolol has similar efficacy, safety, and pharmacokinetics to atenolol in patients with mild to moderate essential hypertension. [ABSTRACT FROM AUTHOR]

A single oral dose of atenolol 100 mg was given to 7 hypothyroid patients (4 F, 3 M), before and after correction of hypothyroidism, mean delay 3.5 months (2 to 6.5 months). There was no change in the elimination parameters of atenolol, but the maximal plasma atenolol concentration was increased (1.66 to 7.37 mg·l) as was the AUC (14.9 to 52.1 mg·l·h) when the hypothyroidism had been treated. Only one patient differed: he had had a supra-selective vagotomy, and had similar curves before and after treatment of the hypothyroidism, both being similar to the plasma concentration curves found in the other patients after correction of the hypothyroidism. The results suggest an increase in the bioavailability of atenolol when hypothyroidism is corrected. The findings in the patient with vagotomy suggest that the decreased bioavailability during hypothyroidism might be related to changes in intestinal pH. Further studies are needed of the impact of hypothyroidism on gastric and pancreatic or biliary function and its consequences for drug absorption, and drug pharmacokinetics. [ABSTRACT FROM AUTHOR]

The efficacy of bopindolol and atenolol in the treatment of patients with chronic stable angina pectoris have been compared in a double blind, randomized study. Both bopindolol 1 mg and atenolol 100 mg for 6 weeks increased mean exercise time (25% and 22%, respectively, compared to placebo), time to angina (27% and 25%), and time to 1 mm of ST-segment depression (32% and 20%). Both drugs reduced ST-segment depression similarly at maximal and submaximal work levels. There was no significant difference in their antianginal efficacy. [ABSTRACT FROM AUTHOR]

A study has been performed in thirteen patients with essential hypertension, WHO Class I-II, and a diastolic blood pressure ≥95 mm Hg, on beta-blocker (metoprolol or atenolol) monotherapy, who were also given felodipine 10 mg b.d. for 28 days. The acute and steady state blood pressure response at rest and during exercise, and the pharmacokinetics of felodipine and metoprolol, were examined. Felodipine in combination with the beta-blocker reduced the systolic and diastolic blood pressures acutely and at steady-state. The duration of the effect was longer at steady-state. There was a significant correlation between the plasma concentration of felodipine and the change in blood pressure. The increase in systolic blood pressure during exercise was of the same magnitude before and after felodipine administration. No change in resting supine heart rate was found after the administration of felodipine. There were no significant differences in the pharmacokinetics of felodipine during long-term treatment, except for the trough plasma concentration, which was increased at steady-state, even though cumulation of felodipine and its metabolite did not occur. There was a significant decrease in the maximal plasma concentration and AUC of metoprolol after 28 days of treatment with felodipine, but its elimination half-life was not changed. The adverse reactions reported during this study were those generally seen after dihydropyridines and, except for two patients who were withdrawn after the first study day, the effects were well tolerated. [ABSTRACT FROM AUTHOR]

The non-specific bronchial reactivity and cough threshold of hypertensive patients on an ACE-I monotherapy regimen (either captopril or enalapril), a β-antagonist monotherapy regimen (either atenolol or metoprolol) or a combination of an ACE-I with a β-antagonist were determined in the present study. Forty-six hypertensives who were on these medications performed a histamine inhalation test (to assess bronchial reactivity) and a further 36 of these individuals participated in the citric acid test (to assess cough threshold). A control cohort consisting of 25 age-matched, drug-free subjects also performed the citric acid test. The incidence of bronchial hyperreactivity was not significantly different between the ACE-I monotherapy regimen and the β-antagonist monotherapy regimen (Chi-squared =0.248). However, when the monotherapy regimens were pooled and compared with the ACE-I and β-antagonist combination regimen, the combination regimen was found to be associated with a significantly higher incidence of bronchial hyperreactivity (Chi-squared =6.69). No difference was observed between the age-matched controls and the hypertensive patients in terms of their cough threshold. [ABSTRACT FROM AUTHOR]

The aim of the present study was to evaluate whether metabolic responses to inhaled salbutamol may be used to measure the cardioselectivity of beta-adrenoceptor antagonists. We therefore studied the effects of oral doses of atenolol 50 mg, 100 mg, 200 mg (A50, A100, A200), propranolol 40 mg (P40), and placebo (Pl) on the hypokalaemic (K) and hyperglycaemic (Glu) responses to inhaled salbutamol in five healthy subjects. Increasing doses of atenolol were associated with a progressive attenuation of ΔK compared with placebo: −0.72 mmol·l (Pl) vs −0.20 mmol·l (A200). However, ΔK with A200 was significantly different from the response with P40: +0.12 mmol·l. There were partial reductions in the hyperglycaemic response with the beta-adrenoceptor antagonists, although this was only significant (compared with Pl) for P40: ΔGlu 1.92 mmol·l (Pl) vs 0.76 mmol·l (P40). These results show that beta-adrenoceptor blockade by atenolol is a dose-dependent phenomenon, which may be measured by the attenuation of salbutamol-induced hypokalaemia. However, beta-adrenoceptor blockade by atenolol 200 mg was less than that by propranolol 40 mg. The glucose response to salbutamol was only partially blocked by propranolol and may therefore not be suitable to assess beta-adrenoceptor antagonism. [ABSTRACT FROM AUTHOR]

The administration of a single dose of atenolol 50 mg 1 h before a standard 3100 kJ cold meal in fasting healthy subjects reduced the supine preprandial heart rate and systolic blood pressure, and blunted the postural and postprandial rises in mean heart rate and systolic blood pressure relative to placebo. It did not affect the preprandial supine diastolic blood pressure, nor the postural rise and postprandial drop in diastolic blood pressure. Preprandial administration of atenolol blunted the postural and postprandial rises in mean plasma renin activity, and it enhanced the rise in plasma noradrenaline during eating in the sitting position, and the postprandial concentrations of noradrenaline. The findings do not permit the conclusion that beta-adrenergic stimulation was the predminant cause of these atenolol-responsive changes. [ABSTRACT FROM AUTHOR]

To investigate if the intrinsic sympathomimetic activity of pindolol could modify its beta-blocking effects on the responses to an adrenaline infusion, 10 healthy volunteers were studied. At an interval of 1-4 weeks each subject received pindolol and atenolol in randomized order before the infusion of adrenaline 0.06 µg·kg·min. Pindolol prevented hypokalaemia and significantly decreased the heart rate during the adrenaline infusion. These effects were not observed after atenolol. The diastolic blood pressure was slightly increased during the infusion of adrenaline after pindolol, whereas it remained unchanged after atenolol. [ABSTRACT FROM AUTHOR]

Six healthy volunteers were given single oral doses of 8 mg salbutamol, 40 mg propranolol, 100 mg atenolol, 8 mg salbutamol plus 40 mg propranolol and 8 mg salbutamol plus 100 mg atenolol, in a placebo controlled study. Plasma potassium fell following salbutamol and rose following atenolol or propranolol, and the hypokalaemic effect of salbutamol was reversed more effectively by propranolol than by atenolol. Although blood glucose rose after salbutamol, it was unaffected by any of the other treatments. Lying and standing pulse rate rose after salbutamol and fell equally after either β-adrenoceptor antagonist, and fell more after salbutamol plus propranolol than after salbutamol plus atenolol. Blood pressure rose after salbutamol and fell after each of the other treatments. Forty milligrams propranolol was thus more effective than 100 mg atenolol in reversing the metabolic effects of 8 mg salbutamol, and was as effective in reversing the cardiovascular effects. In cases of symptomatic salbutamol overdose, propranolol should be considered as an antidote provided the patient is not asthmatic. [ABSTRACT FROM AUTHOR]