Beta blockers and quality of life.

Hypertension is an asymptomatic conditions which can be life threatening. It is thus important that hypertensive patients maintain compliance with their therapy. This can be put at risk if the patient experiences adverse affects or if the patient's lifestyle is significantly altered in some way. The ability to perform daily activities and derive satisfaction is referred to as quality of life. With this in mind the published literature is reviewed here with regard to comparative studies involving beta-blockers. The balance of the evidence reviewed indicates that there are differences in quality of life between ACE inhibitors and the non-selective, lipophilic beta blocker, propranolol, favouring the former. However, this is clearly not a class difference as atenolol, which is beta 1 selective and hydrophilic, results in a similar quality of life profile to that with either captopril or enalapril. This difference between atenolol and propranolol probably arises out of their differing pharmacology, as opposed to any fundamental difference in their blood pressure lowering ability. There are probably too few studies to compare beta blockers and either calcium antagonists or diuretics definitively with regard to quality of life. What little evidence there is suggests a difference between propranolol and verapamil, with the latter giving the better quality of life. However, no difference was observed between verapamil SR and atenolol. Although data are very limited it appears that atenolol impacts more favourably than thiazide diuretics.

A study of the pharmacokinetics and pharmacodynamics of nifedipine in combination with atenolol.

This double-blind randomized, crossover study was undertaken to determine the pharmacokinetic properties of nifedipine retard and atenolol when given separately, as a free or a fixed combination, compared with placebo in 15 healthy male volunteers. There was no difference between the three atenolol formulations in time to maximum blood concentration or elimination half-life. The fixed combination showed significant differences in both maximum observed blood concentrations (+16 per cent) and total area under the curve (+16 per cent) compared to atenolol alone. Urinary recovery of unchanged drug from the fixed combination was also slightly increased but the difference was not statistically significant. Furthermore, statistical evaluation of the plasma pharmacokinetics of nifedipine retard and urinary recovery of nifedipine metabolite showed that all three formulations were indistinguishable. Thus, it is concluded that the fixed combination of nifedipine and atenolol is bioequivalent to the free combination and that the bioavailability of both drugs in the fixed combination is equivalent to that of the single entities.

Atenolol and ischaemic heart disease: an overview.

Data generated to date on the use of beta-blockers, especially atenolol, in ischaemic heart disease are reviewed and compared with the results available with the calcium antagonists. Atenolol appears to be effective as an anti-ischaemic agent in patients with obstructive coronary artery disease when reduction in myocardial oxygen supply (ischaemia not preceded by an increase in heart rate and due presumably to functional coronary stenosis) or increase in demand are the likely causes. Based on current concepts and available data, there is convincing evidence to support the use of atenolol across the spectrum of ischaemic heart disease. In contrast, results with the calcium antagonists have been disappointing and variable. Atenolol, to date, is the only beta-blocker which has been demonstrated to have a life-saving benefit in acute intervention (within 12 hours of onset) in myocardial infarction. This cardioprotective aspect of the drug is likely to be applicable to other areas of ischaemic heart disease, including silent ischaemia.

Long-acting propranolol in the prophylaxis of migraine: a comparative study of two doses.

A randomized double-blind, cross-over study using treatment periods of 12 weeks with a 2-week washout, comparing two long-acting formulations of propranolol ('Inderal' LA 160 mg daily and Half-'Inderal' LA 80 mg daily) was performed after a placebo run-in of 4 weeks on 51 patients. The study indicated that both long-acting formulations were significantly better than placebo in reducing the frequency of migraine attacks (p less than 0.01). After 12 weeks there was a significantly lower (p = 0.03) frequency of migraine attacks in patients on the higher dose formulation than in those on the lower dose formulation. There was no significant difference in the frequency of side effects produced by the two formulations.

Pharmacokinetic and pharmacodynamic studies in man with an antianginal agent 'Visacor'.

This randomized, double-blind, crossover study in 10 healthy male volunteers compared four single oral doses of ICI 141,292 ('Visacor'), i.e. 50, 100, 200, and 300 mg, with placebo. Venous blood samples were collected pre-dose and at various times after dosing and the concentrations of ICI 141,292 in the plasma were determined by radioimmunoassay. A standardized 4-min bicycle exercise test was also performed and before this the resting haemodynamic parameters were assessed. Peak plasma concentrations of ICI 141,292 and the area under the plasma concentration-time curve increased disproportionately with dose such that after scaling to a dose of 200 mg there remained a significant linear trend with dose. The time to peak plasma concentration displayed an increasing trend with dose and, once again, the linear component of this trend was statistically significant. The mean heart rates during exercise were all significantly reduced compared to placebo for 24 h by each of the doses (range 7.8 to 17.4 beats min-1 at 24 h, p less than 0.01). The increase in heart rate during exercise was inversely related to the logarithm of the ICI 141,292 plasma concentration with higher plasma concentrations being associated with lower heart rate increases. The mean supine resting heart rates were slightly but significantly reduced at 2 and 6 h after dosing by each treatment and by the 300 mg dose at 24 h. Each of the doses of ICI 141,292 was well tolerated.

Pharmacokinetics of epanolol in elderly patients with stable angina pectoris.

The pharmacokinetic profile of a single dose of 100 mg of (+/-)-N-[2-[[3-(o-cyanophenoxy)-2-hydroxypropyl]amino]ethyl]- 2-(p-hydroxyphenyl) acetamide (epanolol, Visacor), has been determined in an open study of 15 elderly patients with stable angina pectoris. Haematological, biochemical and physiological measurements demonstrated that epanolol was well tolerated in this group of patients. A mean peak epanolol concentration of 18.4 ng/ml was observed at a mean time of 1.08 h. In about one third of patients, an analytically significant secondary peak was observed. Peak concentrations showed an interindividual variability of 16-fold. Following the peak, plasma concentrations declined biphasically. Epanolol was eliminated from plasma with a mean terminal half-life of 22 h. There was some evidence of a linear relationship between heart rate and logarithmic plasma concentration but this was not statistically significant. These data are consistent with the results of pharmacokinetic studies in healthy young volunteers.

Beta-blockers and central nervous system side effects.

Beta-adrenergic blocking drugs are a widely used, well tolerated and effective treatment for a variety of cardiovascular and noncardiovascular disorders. Over the years, beta-blockers have been associated with an incidence, albeit low, of CNS side effects. The question of interest, however, is whether the incidence is the same for all members of the class or whether other properties, such as hydrophilicity, have a bearing on the incidence of this type of side effect? This article addresses this question. In pharmacokinetic terms the lipophilic beta-blockers have been shown, both in animals and man, to readily cross the blood-brain barrier in contrast to hydrophilic beta-blockers. This is thought to have possible clinical relevance with respect to the relative incidence of CNS side-effects. To clarify the situation every published clinical paper, in which the beta-blockers propranolol (highly lipophilic, nonselective, no intrinsic sympathomimetic activity (ISA)), pindolol (moderately lipophilic, nonselective, moderate ISA), metoprolol (moderately lipophilic, beta 1-selective, no ISA) and atenolol (hydrophilic beta 1-selective, no ISA) were compared, was assessed for information pertaining to CNS side effects. This comprehensive review of the literature has shown, with few exceptions, that the incidence of CNS side effects such as sleep disturbances, dreaming, nightmares and hallucinations following clinically accepted doses of the four beta-blockers under scrutiny is generally low and that effects on short-term memory are minimal or absent. However, within this group of four drugs the incidence of these side effects is lowest with hydrophilic atenolol and generally highest with pindolol and propranolol. Metoprolol occupies an intermediate position. This order is in agreement with the pharmacokinetic observation that the more hydrophilic the molecule, the less is found in the brain tissue of both animals and man, although in the case of pindolol other factors may be important. The clinical relevance of studies involving psychometric testing is not clear.

A comparative pharmacokinetic study of conventional propranolol and long acting preparation of propranolol in patients with cirrhosis and normal controls.

1 Six male patients with alcoholic cirrhosis and seven normal control subjects were each given 80 mg twice daily of conventional propranolol for 1 week and 160 mg once daily of a long acting preparation (LA) of propranolol for 1 week. 2 Plasma propranolol levels were measured at regular intervals on the first and seventh days of both weeks and also following an acute intravenous infusion of 10 mg propranolol on a separate occasion. 3 After the single intravenous dose the elimination half-life tended to be prolonged in the cirrhotic group (median 7.15 h) compared with controls (median 2.92 h) (P = 0.055). 4 After multiple oral dosing with 80 mg twice daily of conventional propranolol the steady-state plasma concentration (Css), area under the curve (AUC tau), peak concentration (Cmax) and trough concentration (Cmin) were significantly higher in cirrhotic patients and the peak: trough ratio (Cmax/Cmin) was significantly lower than controls. 5 After multiple oral dosing with 160 mg LA once daily Cmin was significantly higher than Cmax/min significantly lower in cirrhotic patients; Css, AUC and Cmax were higher than controls but not statistically different. 6 Within both subject groups the bioavailability of 80 mg twice daily of conventional propranolol tended to be greater than 160 mg LA once daily. Cmax was significantly higher in both groups and Css higher in the cirrhotic group with conventional propranolol. 7 In the cirrhotic group the mean reduction in supine heart rate in the steady state was 31.8% with conventional 80 mg twice daily propranolol and 23.75% with 160 mg LA once daily.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioavailability in man of atenolol and chlorthalidone from a combination formulation.

In this comparative bioavailability study in 12 healthy volunteers the blood level profiles and urinary recoveries of both atenolol and chlorthalidone were studied following the administration of the drugs as a fixed combination ('Tenoret 50'), as a free combination, and individually, at doses of 50 mg atenolol and 12.5 mg chlorthalidone. There were no statistically or clinically significant differences between the three treatments of atenolol in terms of individual blood levels, areas under the curve, and urinary excretion. The mean half-lives were between 5 and 7 h, in agreement with other published data. The variation in peak systemic levels is less than that observed for a number of other beta-blocking drugs and is of the same order as seen in other investigations involving atenolol. Thus the bioavailability of atenolol from the fixed combination is equivalent to that from the free combination and from the atenolol tablet. The mean peak blood concentrations of chlorthalidone were 0.94, 1.00, and 0.99 micrograms ml-1 for the fixed and free combinations and the chlorthalidone tablet, respectively. The mean areas under the curve were also similar as were the mean half-lives and urinary recovery. There were no statistically or clinically significant differences between the three treatments. Thus the bioavailability of chlorthalidone from the fixed combination is equivalent to that from the free combination and from the chlorthalidone tablet. It is concluded that combining chlorthalidone and atenolol in a single tablet does not affect the systemic bioavailability of either component.

Tissue atenolol levels following chronic beta-adrenoceptor blockade using oral atenolol in dogs.

Tissue atenolol concentrations are high following chronic continuous beta-adrenoceptor blockade in dogs. Furthermore, significant concentrations of this poorly lipid soluble drug are found within the central nervous system after chronic dosing. It is suggested that all beta-adrenoceptor blocking agents may enter the central nervous system in significant and sufficient quantities to account for a central antihypertensive action of this group of compounds. Sequestration of beta-adrenoceptor agents in the CNS or other tissues may account for other clinically observed effects including adaptive effects.

Theoretical Michaelis-Menten elimination model for propranolol.

A pharmacokinetic model, with Michaelis-Menten elimination, has been developed for drugs and propranolol in particular. The theory is given and the relationship between the area under the theoretical plasma level curve and the absorption rate constant is discussed. This approach allows for an explanation of many of the observed pharmacokinetics of 'Inderal' and particularly 'Inderal' LA; a sustained release preparation of propranolol. In particular, the bioavailability, as measured by area under the curve, is found to be strongly dependent on the absorption half-life in agreement with experimentally observed data.

Atenolol pharmacokinetics in patients on continuous ambulatory peritoneal dialysis.

The elimination of atenolol (20 mg i.v.) has been studied in seven patients with renal failure on continuous ambulatory peritoneal dialysis (CAPD). Although atenolol was eliminated in the peritoneal fluid, the amount recovered in 24 h was relatively low (1.2 +/- 0.15 mg). The calculated urinary (n = 4) and peritoneal (n = 7) clearance was 0.289 +/- 0.058 l/h and 0.152 +/- 0.018 l/h respectively. This was considerably less than calculated total body clearance (1.21 +/- 0.086 l/h). The kinetics of atenolol in CAPD are worthy of further study.

Absolute bioavailability study in the dog with Visacor, a new cardioselective beta blocking drug with intrinsic sympathomimetic activity.

The cardioselective beta-adrenergic blocking drug Visacor (ICI 141,292) was dosed to six beagle dogs in a randomized cross-over manner. Five formulations were examined i.e. a 15 mg/kg intravenous solution, a 50 mg/kg oral solution, and 50, 100 and 200 mg/kg oral powder formulations. Whole blood and urine samples were collected at various times after each dose and analysed for parent drug concentration by a high pressure liquid chromatography procedure. The urine samples were also analysed for parent drug content after hydrolysis with beta-glucuronidase. The normalised intravenous blood levels of ICI 141,292 were found to decay tri-exponentially with a final phase elimination half-life of about 10 h. The computer fitted data showed the drug to possess a high volume of distribution for both the central compartment (54% body weight) and whole body (1384% body weight) indicating the possibility of a high degree of metabolism. The drug clearance following i.v. administration was 196 ml/min and the urinary recovery rate of parent drug was 24% (unhydrolysed) and 40% following hydrolysis with beta-glucuronidase. Following oral dosing at 50 mg/kg (as both powder (C) and solution (B], 100 (D) and 200 (E) mg/kg (as powder) the systemic blood profiles were found to increase with dose. The mean peak blood level attained was 6 +/- 1, 5 +/- 1, 8 +/- 1 and 14 +/- 1 micrograms/ml for formulations, B, C, D and E respectively. The systemic bioavailability of ICI 141,292 was only about 40%. The areas under the curves increased linearly with dose and the elimination phase half-life was unchanged with dose. The calculated half-life (7 h) was apparently shorter after oral administration than after intravenous administration (10 h) but this is probably an artefact dependent on the limit of detection of the assay procedure. At 50 mg/kg there were no significant differences in blood profiles or in the urinary excretion of drug between the solution and powder formulations. However the overall systemic bioavailability was marginally higher with the powder. These observations are consistent for a drug which is cleared by both renal and hepatic elimination processes, which undergoes "first-pass" metabolism on oral dosing and, over the oral dose range studied, obeys linear pharmacokinetics. The significant increase in recovery of parent drug, after hydrolysis of the urine with beta-glucuronidase, indicates that the ICI 141,292 glucuronide conjugate is present to a significant extent. The results also demonstrate that absorption of parent drug from the gastrointestinal tract may not be complete.

Pharmacokinetic studies with atenolol in the dog.

The pharmacokinetics of the cardioselective beta-adrenoreceptor blocking agent atenolol have been determined following intravenous and oral dosing to the dog. After intravenous administration at 200 mg the blood levels of parent drug were found to decay tri-exponentially with a final elimination phase half-life of about 4.5 h. The volume of distribution for the central compartment was 40 per cent body weight and the whole body volume of distribution was 160 per cent body weight. The percentage urinary recovery of parent drug was 83 per cent. Following oral dosing at 400 mg (as a solution and as a clinical trial tablet) the percentage urinary recovery was 65 per cent and the half-life extended slightly to between 5 and 6 h. The peak blood levels were however very similar for the two formulations (17 and 15 micrograms/ml for the solution and tablet respectively) and occurred at the same time (1-2 h after dosing). The total ares under the blood concentration time curves were similar and the values (100 and 104 micrograms/ml-1 h respectively) agreed well with that anticipated on the basis of the intravenous data. It was concluded that the two formulations were bioequivalent and that following oral dosing atenolol was almost completely absorbed with little metabolism or biliary excretion. Following chronic oral dosing at 50, 100, and 200 mg/kg/day the systemic blood levels were found to increase with dose at all time points throughout the study. There was no sex or dose dependency of the half-life and its value on chronic dosing was very similar to that on acute dosing. The dose dependency of the area under the blood concentration time curves was reflected in the plateau blood levels and there was very good agreement between the experimental values and the theoretical relationship based on the acute pharmacokinetic data. In accordance with the half-life there was no accumulation at any of the dose levels studied. Thus it can be concluded that atenolol obeys linear pharmacokinetics over the dose range studied.

Comparative pharmacological and pharmacokinetic observations on propranolol (long acting formulation) and bendrofluazide administered separately and concurrently to volunteers.

1 The effect of long-acting (LA) propranolol, LA propranolol and bendrofluazide, and a new combined formulation of LA propranolol/bendrofluazide (Inderex) on exercise tachycardia was studied in ten normal volunteers. 2 The preparations were given in random order, double-blind, on three separate study weeks. Observations were made 0, 1, 3, 6, 8, 24, 33 and 48 h after drug administration. 3 The three preparations produced a significant reduction in exercise tachycardia up to 48 h after drug administration, and the effects of the three preparations were not significantly different from each other. 4 Following LA propranolol, LA propranolol and bendrofluazide, and the combined formulation the mean reductions in exercise heart rate 24 h after drug administration were 16.7 +/- 2.1%, 13.0 +/- 1.8% and 16.2 +/- 1.7% respectively. 5 Plasma levels of propranolol and bendrofluazide were measured at 0, 1, 2, 3, 6, 8, 10, 12, 24, 33 and 48 h after dose administration. 6 There was no significant difference in plasma propranolol levels, Cmax propranolol or AUCo-x following the three preparations. The mean apparent t1/2 beta of propranolol after LA propranolol alone was significantly shorter than following the other two preparations (P less than 0.05), but this was not associated with a different pharmacodynamic response. 7 There was no significant difference in the pharmacokinetic parameters of bendrofluazide following the two preparations containing bendrofluazide. No bendrofluazide was detected in plasma after LA propranolol alone. 8 The new combined formulation produces similar pharmacodynamic and pharmacokinetic responses to LA propranolol and bendrofluazide given separately, and to LA propranolol given alone, and so may be of value in the treatment of hypertension.

The use of long-acting propranolol ('Inderal' LA) in the management of elderly hypertensive patients.

Fifteen elderly patients whose hypertension was controlled by conventional propranolol 80 mg twice a day had their medication changed to one capsule of 'Inderal' LA (160 mg) daily. The blood pressure, heart rate and propranolol concentrations were measured at various time points when the patients were receiving the conventional preparation and these assessments were repeated when the long-acting preparation was administered. Although the heart rate was lower with conventional propranolol than with 'Inderal' LA there was no significant difference in the blood pressure levels. The mean peak blood level of propranolol was, however, significantly lower with 'Inderal' LA compared with conventional propranolol and occurred later. At 12 h the plasma propranolol levels were higher after 'Inderal' LA then following the intake of conventional propranolol (p less than 0.01); there was no difference in the plasma levels at 24 h. The area under the concentration time curve was significantly higher on conventional propranolol. Compared with published data, the plasma levels were higher than those in younger patients. 'Inderal' LA was well tolerated and side effects were minimal.

Percutaneous absorption of chlorhexidine in neonatal cord care.

The percutaneous absorption of chlorhexidine during its routine use in topical antiseptic preparations used in umbilical cord care was investigated by determining plasma chlorhexidine concentrations at ages 5 and 9 days. These showed that percutaneous absorption of chlorhexidine occurred in preterm neonates treated with a 1% solution of chlorhexidine in ethanol, but not in term infants similarly treated, or in preterm infants treated only with a dusting powder containing 1% chlorhexidine and 3% zinc oxide.

Atenolol in the treatment of pregnancy-induced hypertension.

1 The pharmacological properties of atenolol suggest its possible usefulness in pregnancy-induced hypertension. The pharmacokinetics of atenolol in the pregnant woman, concentrations in cord blood, and its effects on maternal blood pressure and the foetus, are evaluated. 2 We studied 13 pregnant women with hypertension, most of them uncontrolled on methyldopa. Whole blood concentrations and urinary excretion of the drug were measured over 24 h following a 100 mg dose. Effects on maternal blood pressure, pulse rate and foetal heart rate and cardiotocograph were compared for the 4 days before treatment and the first 4 days of treatment. The birth weights and Apgar scores of the babies were recorded. 2 The pharmacokinetics of atenolol (plasma half-life of about 8 h) in pregnant women do not differ from the findings in the non-pregnant. The levels of atenolol in the cord blood were confirmed as approximately equal to those in the maternal blood. 4 In the ten women in whom blood pressure was assessed a small significant fall in blood pressure was observed. 5 A 5% mean fall in foetal heart rate resulted but in one case was a rate below 120 beats/min recorded. There was no evidence of depression of the stress response of the foetal heart. Apgar scores 5 min post partum were satisfactory. 6 Atenolol appears to be safe for use in hypertensive pregnancies. Its effectiveness as an antihypertensive agent in pregnancy requires further controlled evaluation.