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PubMed2003

Propranolol plus placebo versus propranolol plus isosorbide-5-mononitrate in the prevention of a first variceal bleed: a double-blind RCT.

Nonselective beta-blockers are very effective in preventing first variceal bleeding in patients with cirrhosis. Treatment with isosorbide-5-mononitrate (IS-MN) plus propranolol achieves a greater reduction in portal pressure than propranolol alone. The present multicenter, prospective, double-blind, randomized, controlled trial evaluated whether combined drug therapy could be more effective than propranolol alone in preventing variceal bleeding. A total of 349 consecutive cirrhotic patients with gastroesophageal varices were randomized to receive propranolol + placebo (n = 174) or propranolol + IS-MN (n = 175). There were no significant differences in the 1- and 2-year actuarial probability of variceal bleeding between the 2 groups (propranolol + placebo, 8.3% and 10.6%; propranolol + IS-MN, 5% and 12.5%). The only independent predictor of variceal bleeding was a variceal size greater than 5 mm. However, among patients with varices greater than 5 mm (n = 196), there were no significant differences in the incidence of variceal bleeding between the 2 groups. Survival was also similar. Adverse effects were significantly more frequent in the propranolol + IS-MN group due to a greater incidence of headache. There were no significant differences in the incidence of new-onset or worsening ascites or in impairment of renal function. In conclusion, propranolol effectively prevents variceal bleeding. Adding IS-MN does not further decrease the low residual risk of bleeding in patients receiving propranolol. However, the long-term use of this combination drug therapy is safe and may be an alternative in clinical conditions associated with a greater risk of bleeding.

Adrenergic beta-Antagonists↗
PubMed1982

Propranolol in angina pectoris. Comparison of long-acting and standard-formulation propranolol.

In a double-blind, crossover study in 20 patients with stable angina pectoris, the effects of long-acting propranolol, 160 mg administered once daily for 4 weeks, were compared with those of standard propranolol, 40 mg given four times daily for 4 weeks. The patients suffered no adverse effects when they were switched between treatment schedules. The average number of episodes of angina during the 4 weeks on long-acting propranolol was 7.3 and on standard propranolol. 6.3. Average nitroglycerin consumption was 5.8 and 4.9 tablets during therapy with these two drug programs. The resting values for heart rate, systolic blood pressure and rate-pressure product were similar when determined 25.4 hours after a dose of long-acting propranolol and 10.7 hours after standard propranolol. When the patients exercised at these times, patients on long-acting propranolol and standard propranolol had similar walking times to the onset of angina and to the development of moderate angina. The values for heart rate, systolic blood pressure and rate-pressure product were similar at rest and during exercise during these two treatment programs. We conclude that long-acting propranolol administered in a dose of 160 mg daily is as effective as 50 mg of standard propranolol four times daily.

Angina Pectoris↗
PubMed1996

Relationship between the amount of propranolol permeating through the stratum corneum of guinea pig skin after application of propranolol adhesive patches and skin irritation.

In the present study we evaluated the relationship between the cumulative amount of propranolol permeating through the stratum corneum and the formation of erythema, a skin irritation reaction, after transdermal application of adhesive patches containing propranolol to the skin of guinea pigs. The intensity of erythema was expressed in terms of a* values measured with a chromameter. The a* values increased in guinea pigs after application of the adhesive patches containing 0.4 mg/cm2 of propranolol to the skin. Since the adhesive patches showed good adhesion to the skin (propranolol content is less than the saturated concentration in the adhesive base) and the cumulative amount of propranolol permeating through the stratum corneum is small, the development of erythema was considered to be mainly due to physical factors such as peeling. Even in adhesive patches containing 0.8 mg/cm2 or 1.2 mg/cm2 of propranolol, a* values increased, although adhesion to the skin is low because of crystallization of propranolol in the adhesive base. On the other hand, in these two adhesive patches, the cumulative amount of propranolol permeating through the stratum corneum increased up to 24 h after application. These findings suggest that the skin irritation reaction is due to propranolol mainly absorbed transdermally, because there is a high correlation between the cumulative amount of propranolol permeating through the stratum corneum and the a* values (r = 0.928).

Administration, Cutaneous↗
PubMed1991

Propranolol compared with propranolol plus isosorbide-5-mononitrate for portal hypertension in cirrhosis. A randomized controlled study.

OBJECTIVE: To investigate whether isosorbide-5-mononitrate (Is-5-Mn) given with propranolol reduces hepatic portal pressure more than does propranolol alone in patients with cirrhosis. DESIGN: A randomized controlled trial. PATIENTS: Fifty patients with cirrhosis and esophageal varices entered and 42 completed the study. INTERVENTION: Twenty-one patients received oral propranolol at increasing doses until their resting heart rate was reduced by 25%, and 21 patients received oral propranolol (on the same schedule) plus oral Is-5-Mn, 40 mg twice a day. MEASUREMENTS: Hepatic vein pressure gradient, liver function, and splanchnic and systemic hemodynamics before and after 3 months of continuous therapy. MAIN RESULTS: At 3 months, the hepatic venous pressure gradient decreased more (P less than 0.01) in patients given propranolol plus Is-5-Mn (19%, from 18.4 +/- 3.9 to 14.9 +/- 3.8 mm Hg; 95% CI, -2.4 to -4.5 mm Hg) than in those given propranolol alone (10%, from 18.2 +/- 3.5 to 16.3 +/- 3.1 mm Hg; CI, -1.1 to -2.7 mm Hg). The hepatic venous pressure gradient decreased by more than 20% of the baseline value in 10% of patients receiving propranolol, but in 50% of patients receiving combined therapy (P less than 0.02). There were statistically significant decreases in hepatic blood flow and the intrinsic clearance of indocyanine green after propranolol therapy, but not after combined therapy. The treatments caused similar reductions in azygos blood flow and cardiac output. CONCLUSIONS: The long-term combined administration of propranolol plus Is-5-Mn reduces portal pressure more than propranolol alone without adverse effects on hepatic perfusion and liver function. Whether this greater hemodynamic effect translates into better clinical efficacy should be determined in randomized controlled trials.

Aged↗
PubMed1980

Pharmacokinetics of propranolol isomers and their relationships with beta adrenoceptor blocking activity in rabbits administered with dl-propranolol.

Plasma concentrations of dl- and l-propranolol were determined in rabbits after the i.v. injection of 200, 400 and 800 micrograms/kg of dl-propranolol. The data conformed to a biexponential equation. The beta adrenoceptor blocking activity was measured by the percent reduction in isoproterenolol-induced tachycardia after the administration of dl-propranolol. The l-isomer had a longer plasma half-life than dl-propranolol at each dose during the beta-phase. At a dose of 800 micrograms/kg, both dl- and l-propranolol had longer plasma half-life than those of 200 and 400 micrograms/kg doses and a smaller total plasma clearance was observed to 800 micrograms/kg, although statistically not significant. At steady state, plasma concentrations of both dl- and l-propranolol correlated well with beta adrenoceptor blocking activity (r = 0.913 for dl-propranolol and r = 0.939 for the l-isomer). These results demonstrate that after the administration of the racemic drug l-propranolol had a longer plasma half-life. The plasma concentration of dl- and l-propranolol is a good parameter for beta adrenoceptor blocking activity. The pharmacologic activity of propranolol at the highest dose persists longer than expected, probably due to hemodynamic alterations, which causes a decrease in liver blood flow with the resultant reduction in the elimination rate of the drug.

Adrenergic beta-Antagonists↗
PubMed1981

Essential tremor treated with propranolol: lack of correlation between clinical effect and plasma propranolol levels.

Five patients with essential tremor were treated with increasing daily doses of propranolol. Tremor intensity was assessed after each propranolol dose had been given daily for a period of at least seven days. The evaluation was made 12 to 15 hours after the last propranolol ingestion. It included a semiquantitative clinical tremor evaluation and quantitative registration with an accelerometer. Electronic integration of the accelerometer curves gave an arbitrary measure of tremor intensity. Plasma propranolol concentration was determined at each tremor measurement. The reduction in tremor correlated with increasing propranolol doses, whereas plasma propranolol concentrations varied widely among individuals and could not be correlated with tremor reduction. Most of the patients had considerable diminution in tremor at low propranolol doses, often with an unmeasurable plasma propranolol concentration. Determination of plasma concentrations has little value in long-term treatment of essential tremor with propranolol. The dosage can be sufficiently guided by clinical evaluation of effect.

Adult↗
PubMed1988

Comparative study of the effects of acebutolol, atenolol, d-propranolol and dl,-propranolol on the alterations in energy metabolism caused by ischemia and reperfusion: a 31P NMR study on the isolated rat heart.

31-P NMR spectroscopy data recorded for the isolated heart were analyzed, in conjunction with functional and biochemical variables, in order to investigate the effect observed for several different beta-adrenoceptor antagonists or the alterations provoked by global partial ischemia (37 degrees C, 24 minutes, 1% residual coronary flow) and reperfusion in the metabolism of the myocardium. During ischemia: intracellular acidosis, adenosine triphosphate (ATP) degradation, and inorganic phosphate (Pi) accumulation were found to be reduced whether the perfusion fluid contained: acebutolol 2.7 x 10(-5) M, atenolol 10(-5) M, d-propranolol 10(-5) M, or dl-propranolol 10(-5) M. On reperfusion metabolic and functional variables were variously affected by the different drugs, except the Pi level which was, in all series, significantly lower compared with control hearts. The adenylate charge and the glycogen stores were protected in the acebutolol, dl-propranolol, and d-propranolol groups. The ATP level was higher than in controls only in the acebutolol and atenolol groups. The intracellular pH recovered to values nonsignificantly different from preischemic values in the acebutolol and dl-propranolol-treated hearts only. The mechanical performance, expressed as the rate-pressure product, was unaltered by the ischemia-reperfusion sequence in the acebutolol and d-propranolol series, while decreasing significantly in controls and in the atenolol group. In dl-propranolol-treated hearts the mechanical activity, which in normoxic conditions was already halved during the effect of the drug, remained at this same level after ischemia. From these observations, it appears that the nonspecific properties of the drugs, as distinct from beta-blockade, play an important part in attenuating the ischemia-induced alteration in myocardial metabolism. Thus, it can be postulated that (1) the metabolic effects of dl-propranolol probably result largely from the reduction of heart work induced by this drug; (2) the maintenance of energy metabolism associated with the preservation of the myocardial activity, as observed in the case of acebutolol and d-propranolol, is possibly a consequence of the existence of a membrane-stabilizing activity.

Acebutolol↗
PubMed1985

Clinical and hemodynamic effects of combined propranolol and nifedipine therapy versus propranolol alone in patients with angina pectoris.

To determine the comparative effectiveness and hemodynamic effects of long-term oral treatment with propranolol alone and combined with nifedipine in patients with stable angina pectoris, 20 patients with coronary disease were studied by equilibrium radionuclide ventriculography. Measurements were performed at rest and during supine bicycle exercise before treatment, after 4 weeks on propranolol, 1 hour after institution of combined propranolol and nifedipine treatment, and after 4 weeks on the combined treatment. The reduction in exercise rate-pressure product induced by the combination (17.2 +/- 2.6 X 10(3)) was significantly greater (p less than 0.001) than that attained by propranolol alone (19.3 +/- 2.8 X 10(3)). In patients at rest, neither propranolol nor the combined therapy altered global left ventricular (LV) ejection fraction (EF). Without drugs and on propranolol, exercise EF decreased significantly. On the combined therapy there was a significant improvement in exercise EF compared both with rest values (p less than 0.01) and with exercise EF on propranolol (p less than 0.001). Exercise tolerance, expressed as total work load, significantly increased on propranolol and further increased on combined therapy. Thus the combined propranolol/nifedipine therapy in patients with stable angina proved to be hemodynamically superior to therapy with propranolol alone and safe even in patients with moderately depressed LV function.

Administration, Oral↗
PubMed1983

Propranolol, propranolol glucuronide, and naphthoxylactic acid in breast milk and plasma.

High-performance liquid chromatographic assays for propranolol and its major metabolites in plasma and breast milk are described. The breast milk/whole plasma ratios of propranolol in three lactating women were in the range of 0.33 to 1.65. The half-life of elimination of propranolol from breast milk was 6.5 +/- 3.4 h (mean +/- SD), which was significantly longer (t = 1.844, df = 4, p less than 0.01) than the half-life of elimination of propranolol from plasma, which was 2.6 +/- 1.2 h (mean +/- SD). The half-life of elimination of the propranolol metabolite naphthoxylactic acid from breast milk was 4.2 +/- 0.9 h (mean +/- SD), which was not significantly different (t = 0.042, df = 4, p greater than 0.05) from the mean half-life of elimination from plasma, which was 4.2 +/- 1.2 h (mean +/- SD). The penetration of propranolol glucuronide into breast milk was slower and to a lesser extent than that of propranolol and naphthoxylactic acid. The maximum dose, calculated from the results presented in this paper, ingested as either propranolol or as propranolol glucuronide in breast milk by the neonate would be less than 0.1% of the maternal dose.

Female↗
PubMed1982

Plasma levels of (+) and (-)-propranolol and 4-hydroxypropranolol after administration of racemic (+/-)-propranolol in man.

1 We have given fifteen healthy volunteers single doses of racemic (+/-)-propranolol orally (40 mg) and intravenously (5-10 mg) to find out how large the variation was of the ratio between (-)- and (+)-propranolol plasma levels in relation to that of total levels of propranolol and 4-hydroxypropranolol. 2 Total propranolol (+/-)-levels 2 h after a 40 mg oral dose of (+/-)-propranolol varied from 21 to 580 nmol/l and those of 4-hydroxypropranolol from 0 to 33 nmol/l. Their levels did not correlate. The ratio between (-)- and (+)-propranolol levels varied from 0.99 to 2.04. The plasma half-lives of the two isomers were usually similar. 3 We conclude that in most single doses studies on relationships between plasma concentrations and effects (beta-adrenoceptor blockade) it is not necessary to quantitate (+)- and (-)-propranolol levels separately since total (+/-) plasma propranolol levels varied much more than the ratio between (-)- and (+)-propranolol.

Administration, Oral↗
PubMed1980

D-propranolol and DL-propranolol both decrease conversion of L-thyroxine to L-triiodothyronine.

The effects of propranolol (DL-propranolol) and D-propranolol on thyroid hormone metabolism were studied in six euthyroid volunteers receiving L-thyroxine (T4) and six hypothyroid patients receiving T4 replacement. D-propranolol as well as propranolol decreased L-triiodothyronine (T3) concentrations and the ratio of T3 to T4 in the euthyroid subjects, and D-propranolol decreased these variables in the subjects with hypothyroidism (propranolol was not given to this group). It is concluded from this study and from parallel invitro investigations that the effect of propranolol on the conversion of T4 to T3 is unrelated to its beta-adrenergic blocking activity, and that at low therapeutic doses propranolol may exert appreciable "membrane-stabilising" effects in vivo.

Aged↗
PubMed1995

Toxicokinetics of a single intravenous dose of rac-propranolol versus optically pure propranolol in the rat.

Conscious male Wistar SPF Riv:TOX rats were dosed intravenously with 2.5, 5, or 10 mg/kg rac-propranolol.HCl, or with 5 mg/kg of either (-)-(S)- or (+)-(R)-propranolol.HCl. Disposition of (-)-(S)- and (+)-(R)-propranolol after dosing of rac-propranolol was linear in the dose range examined. Total plasma clearance was not changed in animals dosed with the individual enantiomers compared to the animals that were dosed with rac-propranolol. However, for (-)-(S)-propranolol both volume of distribution and elimination half-life decreased, whereas for (+)-(R)-propranolol increases were observed for these characteristics, in animals dosed with the individual enantiomers. Our observations suggest that the (+)-(R)-enantiomer competes with (-)-(S)-propranolol for plasma protein binding sites, resulting in lower plasma protein binding of the (-)-(S)-enantiomer when the racemate is administered. From recent toxicological experiments, it was concluded that rac-propranolol is more toxic than the individual enantiomers in the rat, when dosed iv at the same total mass. It is concluded that the observed potentiation of toxic effects of propranolol enantiomers when administered as a racemate can at least partly be explained by a pharmacokinetic interaction.

Adrenergic beta-Antagonists↗
PubMed1992

Beta-blockers: propranolol, metoprolol, atenolol, pindolol, alprenolol and timolol, manifest atherogenicity on in vitro, ex vivo and in vivo models. Elimination of propranolol atherogenic effects by papaverine.

The addition of the beta-blockers propranolol, metoprolol, atenolol, pindolol, alprenolol and timolol to a culture of peritoneal macrophages or smooth muscle cells induced an increase in the intracellular cholesterol content. Blood serum obtained from a rabbit after a peroral administration of beta-blockers also induced cholesterol accumulation. This property of drug or blood serum obtained after peroral administration is conventionally referred to as atherogenic potential or atherogenicity. Regular administration of propranolol during a 21-day period evoked stable atherogenicity of rabbit blood serum. This was accompanied by stimulation of manifestations of atherosclerosis in the aorta deendothelialized with a balloon catheter. Propranolol increased neointimal thickening, lipid accumulation, an increase in cell number and in the collagen content. In vitro, the combination of propranolol with papaverine eliminated the atherogenic effect of propranolol which manifested itself as stimulation of cholesterol accumulation in cultured cells. Simultaneous peroral administration of propranolol and papaverine prevented the appearance of serum atherogenicity. Papaverine eliminated neointimal thickening, an increase in cell number and in the lipid and collagen contents evoked by propranolol. Papaverine itself had no effect on these parameters. Thus, the atherogenicity of propranolol as well as capacity of papaverine to eliminate beta-blocker atherogenicity revealed in cell culture was confirmed in vivo. We hope that these results may be useful in the development of new drugs and optimization of antiatherosclerotic drug therapy.

Adrenergic beta-Antagonists↗
PubMed1985

Nadolol, propranolol, and thyroid hormones: evidence for a membrane-stabilizing action of propranolol.

Ten normal subjects participated in a placebo-controlled, randomized, parallel study to determine the effects on thyroid hormones of chronic (4 wk) propranolol or nadolol, including observation for 2 wk after their discontinuation. Subjects took placebo for 1 wk, then propranolol or nadolol doses increased weekly to 240 mg/day by 3 wk. After 1 wk of placebo, after 2 wk of the highest dose of propranolol or nadolol, and 2, 4, 6, 9, and 13 days after their discontinuation, thyroid hormone levels were measured by radioimmunoassay and heart rate responses to exercise were assessed. Both drugs induced equal and high degrees of exercise tachycardia inhibition. Propranolol decreased 3,3'5-triiodothyronine (T3) levels, increased 3-3'-5'-triiodothyronine (rT3) levels, tended to increase thyroxine levels, but did not increase thyroid-stimulating hormone levels. After discontinuation of propranolol, rT3 levels slowly (day 6) returned to values after placebo, suggesting delayed recovery of 5'-deiodination. There was no evidence of any rebound in T3 levels after withdrawal of propranolol. Nadolol induced no significant changes in the thyroid hormones measured. The data agree with the known effects of propranolol on thyroid hormones in normal man and show that nadolol does not have these effects when given chronically at an equivalent beta-blocking dose. The likely explanation is that the membrane-stabilizing activity of propranolol alters thyroid physiology by interfering with 5'-deiodinase.

Adult↗
PubMed2000

Endoscopic sclerotherapy plus propranolol versus propranolol alone in the primary prevention of bleeding in high risk cirrhotic patients with esophageal varices: a prospective multicenter randomized trial.

BACKGROUND: Analysis of primary prevention studies of the use of beta-blockers has shown clear reductions in variceal bleeding in cirrhotic patients with varices. In contrast, the usefulness of prophylactic endoscopic sclerotherapy, alone or in combination with propranolol, in the management of these patients is still under investigation. The present study compared the efficacy of combined sclerotherapy and propranolol versus propranolol alone in the primary prevention of hemorrhage in cirrhotic patients with varices and high (greater than 18 mm Hg) intraesophageal variceal pressure. METHODS: Patients were randomly assigned to propranolol (42 patients) or to propranolol plus sclerotherapy (44 patients). The mean duration of follow-up was 26.8 +/- 7.7 and 24.6 +/- 9.8 months, respectively. RESULTS: During this period 23% of the patients in the combination group experienced at least 1 episode of bleeding due to varices or congestive gastropathy as compared with 14% in the propranolol group (not significant). Twenty-three patients (52%) in the combination group developed complications as compared with 8 (19%) in the propranolol group (p = 0.002). The mortality rate was similar in both groups (14% and 18%, respectively). The only independent factor predictive of survival was the level of serum albumin. CONCLUSIONS: Endoscopic sclerotherapy should not be used for the primary prevention of hemorrhage in cirrhotic patients at high risk of variceal bleeding who are undergoing treatment with propranolol.

Adrenergic beta-Antagonists↗
PubMed1987

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)

Adult↗