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PubMed1982

Propranolol dosage, plasma concentration, and beta blockade.

One hundred sixty-nine normal men received varying propranolol dosage regimens and placebo. Dose level and frequency were compared with plasma propranolol levels and beta blockade, as assessed by reduction of exercise tachycardia. Propranolol levels above 20 ng/ml induced significant beta blockade. An average daily propranolol dose slightly in excess of 160 mg led to a minimum plasma level above 20 ng/ml. Approximately 50% of subjects achieved 20 bpm or greater decrease in exercise tachycardia with 160 mg per day. The degree of beta blockade at the daily minimum propranolol level was related to dose and not dose frequency. The relation of propranolol dose and plasma levels to beta blockade in normal subjects appears to reflect observations in large clinical trials.

Adolescent↗
PubMed1983

Glucose and lipid metabolism during acebutolol and propranolol therapy of angina in nondiabetic patients.

The metabolic effects of acebutolol, a cardioselective beta-adrenergic blocker, and of propranolol, a nonselective beta blocker, were evaluated. Our subjects were 20 men with chronic stable angina; none had diabetes. An initial 4-wk, single-blind control phase was followed by two drug treatment periods, each a 3-wk double-blind titration phase (using increasing doses of acebutolol or propranolol), followed by a 5-wk double-blind maintenance phase. Metabolic studies were performed at the end of the control and maintenance phases. Propranolol induced elevation in basal serum glucose concentrations and both propranolol and acebutolol decreased glucose tolerance at 2.5 and 3 hr. There was no noticeable effect on insulin secretion by either drug. Neither propranolol nor acebutolol induced hyperlipidemia. There was a small decrease in total serum cholesterol after propranolol. Both drugs decreased low-density lipoprotein cholesterol. No effects were noted on the levels of serum triglycerides, high-density lipoprotein cholesterol, or free fatty acids.

Acebutolol↗
PubMed1983

Effect of thyrotoxicosis on liver blood flow and propranolol disposition after long-term dosing.

The effects of thyrotoxicosis on Liver blood flow and propranolol disposition were followed in five patients while thyrotoxic and when euthyroid. Propranolol was taken orally to achieve steady state and then radiolabeled drug was given simultaneously by intravenous injection. Thyrotoxicosis was associated with doubling of both oral and systemic clearances of unbound propranolol, which resulted in an approximately 50% reduction in blood concentrations after oral doses. These changes were attributable to increases in hepatic blood flow and drug-metabolizing activity of the liver. The propranolol elimination t 1/2 was not affected by thyrotoxicosis since the enhanced clearance was offset by a change in volume of distribution. These findings may explain the reduction of plasma propranolol concentration and many of the therapeutic failures reported in the treatment of thyrotoxicosis. The dose required to achieve therapeutic blood concentrations of propranolol in thyrotoxic patients is variable and will usually be substantially larger than that required for euthyroid patients.

Administration, Oral↗
PubMed1985

Propranolol: pooled Michaelis-Menten parameters and the effect of input rate on bioavailability.

Average steady-state propranolol plasma concentration (Css) were calculated from published steady-state propranolol clearance data for dose rates (Ro) of 40, 80, 160, 240, and 320 mg/ day in divided doses every 6 hours. The Css-Ro data for each of four subjects were fit essentially perfectly by the equation: Css = KmRo/ (Vm-Ro). Very similar Vm and Km values were obtained with the Vmi and Kmi values for four parallel Michaelis-Menten pathways of propranolol metabolism. It is shown by use of the mean Vm and Km values that the propranolol input rate profoundly affects its bioavailability, which is expected for a first-pass drug that follows Michaelis-Menten elimination kinetics after oral dosing. This most likely explains the poor bioavailability of propranolol after a sustained-release formulation. The decreased bioavailability of propranolol when the number of subdivisions of the daily dose is increased is also explained.

Administration, Oral↗
PubMed1986

Food effects on propranolol systemic and oral clearance: support for a blood flow hypothesis.

The influence of a high-protein meal as compared to fasting on the disposition of simultaneous intravenous and oral doses of propranolol, as well as on indocyanine green clearance, was examined in six normal subjects. The intravenous dose (0.1 mg/kg) was unlabeled propranolol and the oral dose (80 mg) was a stereospecifically deuterium-labeled pseudoracemate of propranolol. Systemic clearance of propranolol increased 38%, from 1005 +/- 57 to 1384 +/- 115 ml/min (mean +/- SE; P less than 0.05) as a result of the meal, with no change in t1/2 or apparent volume of distribution. A 12% decrease in oral clearance occurred with the meal but was not statistically significant (3717 +/- 185 ml/min, fasting; 3245 +/- 498 after meal), whereas bioavailability increased 67% (27.2% +/- 1.7% fasting; 45.5% +/- 4.3% after meal; P less than 0.01). Estimated hepatic blood flow, as measured by indocyanine green clearance, rose 34% 60 minutes after the meal (1719 +/- 155 ml/min fasting; 2304 +/- 218 ml/min after meal; P less than 0.02). A difference was observed in the oral clearance of the propranolol enantiomers in the fasting state, but this difference was unaffected by the meal. These alterations in propranolol disposition, as the result of a high-protein meal, are consistent with a transient increase in hepatic blood flow.

Administration, Oral↗
PubMed1987

The effects of verapamil and propranolol on exercise tolerance in hypertensive patients.

In a single-blind, placebo-controlled crossover study the effects of verapamil (450 +/- 30 mg/day) and propranolol (160 +/- 20 mg/day) on endurance time during submaximal exercise were compared in eight patients with essential hypertension. The drugs were given in randomized order. Each active drug period was preceded by a placebo phase. Endurance tests were performed during both placebo periods and treatment with verapamil and propranolol by bicycle ergometry. Both drugs were equally effective in decreasing resting blood pressure. Verapamil and propranolol reduced exercise heart rate, the effect of propranolol being more pronounced. With placebo, endurance time during exercise was 57 +/- 11 minutes; with propranolol it was 32 +/- 7 minutes (P less than 0.05). Verapamil had no influence on endurance time. The study demonstrates that in contrast to propranolol, verapamil has no influence on exercise tolerance during submaximal work in patients with hypertension.

Adult↗
PubMed1989

Propranolol's metabolism is determined by both mephenytoin and debrisoquin hydroxylase activities.

The relative contributions of the debrisoquin and mephenytoin isozymes of hepatic cytochrome P-450 to the stereoselective metabolism of propranolol have been studied in a panel of volunteers of known oxidative phenotypes. Six subjects were extensive metabolizers of both debrisoquin and mephenytoin (EM). Four subjects were poor metabolizers of debrisoquin but rapid for mephenytoin (PMD). Five subjects were poor metabolizers of mephenytoin but rapid for debrisoquin (PMM), and one individual had a deficiency for both test compounds (PMD/M). Partial metabolic clearances of each propranolol enantiomer to 4-hydroxypropranolol (4-OH-P), the sulfate, and glucuronide conjugates of 4-OH-P, naphthoxylactic acid (NLA) and propranolol glucuronide, were estimated after a single oral dose of racemic propranolol (80 mg). The partial metabolic clearance of both enantiomers to total 4-OH-P in the PMD group was 75% less than in the EM and PMM groups, indicating the contribution of the debrisoquin isozyme to this route of metabolism. The R/S ratios for the clearance to 4-OH-P were similar between EM and PMD (2.5 +/- 0.5 vs 2.5 +/- 0.4, respectively), implying that the different enzymes involved in ring hydroxylation (i.e., the debrisoquin isozyme and other hydroxylases) have similar stereoselective preferences. The partial metabolic clearance to NLA was 55% less in the PMM group than in the EM and PMD groups, indicating that S-mephenytoin 4-hydroxylase contributes to the metabolic conversion of propranolol to NLA. The R/S ratios for the clearance to NLA were close to unity in all groups. The partial metabolic clearance to propranolol glucuronide also did not exhibit stereoselectivity and was similar in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Aryl Hydrocarbon Hydroxylases↗
PubMed1991

Increased suppression of exercise-induced increase in renin by propranolol in Chinese subjects.

Sensitivity to the hypotensive effect of propranolol differs between Chinese subjects and white subjects. To explore the pharmacodynamic explanation for this difference, eight Chinese subjects (age range, 25 to 42 years) and eight white subjects (age range, 22 to 36 years) were given single doses of 10, 20, 40, and 80 mg propranolol on separate occasions at least 3 days apart. Heart rate, mean blood pressure, norepinephrine, epinephrine, and plasma renin activity were measured at the end of treadmill exercise 2 hours after medication was administered. Propranolol produced a concentration-dependent reduction in mean blood pressure and heart rate in both groups. Concentration-response curves were shifted significantly to the left in Chinese subjects, confirming the increased sensitivity to propranolol of the Chinese. The baseline exercise plasma renin activity was twofold higher (p less than 0.05) in Chinese than in white subjects. The sensitivity to beta-blockade-induced suppression of plasma renin activity was increased in the Chinese, which resulted in a sevenfold higher concentration being required in white subjects than in Chinese to produce the same 50% suppression of exercise plasma renin activity (84.8 +/- 23.2 versus 12.7 +/- 7.4 ng/ml, p less than 0.05). The reduction in exercise heart rate and mean blood pressure produced by propranolol were well correlated to the reduction in exercise plasma renin activity in both populations. There was no significant effect of either race or propranolol on plasma catecholamine concentration after exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1998

The inhibitory effect of propranolol on ATP-sensitive potassium channels in neonatal rat heart.

1. Whole cell and single channel recordings of ATP-sensitive K+ current (I(K,ATP)) were carried out in ventricular myocytes isolated from neonatal rat hearts. 2. (+/-)-Propranolol, a commonly used beta-blocker, inhibited the whole cell I(K,ATP) in a concentration-dependent manner with a half-maximal concentration (IC50) of 6.7 +/- 1.4 microM, whereas it blocked the inward rectifier K+ current (I(K,I)) only at much higher concentrations (IC50 = 102.4 +/- 20.2 microM). The inhibition was time- and voltage-independent. 3. In the outside-out patch configuration, (+/-)-propranolol inhibited I(K,ATP) (IC50 = 9.8 +/- 2.9 microM) by decreasing the open probability of the channel without inducing additional noise in the open-channel current or a decrease of single channel conductance. The single channel current of I(K,I) was also blocked by (+/-)-propranolol in the same way as I(K,ATP). 4. (+)-Propranolol, an optic isomer having no beta-blocking effect, inhibited I(K,ATP) (IC50 = 5.8 +/- 1.0 microM), whilst atenolol, a selective beta1-blocker had no effect. Neither GDPbetaS (1 mM) nor GTPgammaS (200 microM) included in the pipette solution modulated the inhibitory effect of (+/-)-propranolol. 5. We concluded that the inhibitory effect of (+/-)-propranolol was not via the beta-adrenergic signal transduction pathway, but by direct inhibition of I(K,ATP) channels.

Adenosine Triphosphate↗
PubMed1998

Effects of chronic application of propranolol on beta-adrenergic signal transduction in heart ventricles from myopathic BIO TO2 and control hamsters.

1. In human congestive heart failure beta-adrenoceptor antagonists improve exercise tolerance and cardiac contractility. These beneficial effects are thought to reflect an up-regulation of cardiac beta-adrenoceptors, involving mainly the beta1-subtype. In the present study we evaluated the functional contribution of beta-adrenoceptor subtypes to stimulation of adenylyl cyclase in an animal model of dilated cardiomyopathy, and compared the effects of treatment with propranolol on cardiac beta-adrenergic signal transduction in myopathic and control hamsters. 2. Cardiomyopathic BIO TO2 hamsters and BIO F1B controls aged 270 days were used. In the treatment study, hamsters received drinking water with or without propranolol 40 mg kg(-1) d(-1) for 4 weeks prior to sacrifice. Density and subtype distribution of beta-adrenoceptors were determined in radioligand binding studies. Functional contributions of beta-adrenoceptors were evaluated by subtype-selective stimulation of adenylyl cyclase. Cardiac G-protein content was determined by immunoblotting. 3. Compared to BIO F1B controls, myopathic hamsters showed increases in cardiac total beta- and beta2-adrenoceptor density, G(s alpha) and G(i alpha) content. In BIO TO2 ventricles, beta1-adrenoceptors were almost completely uncoupled from adenylyl cyclase stimulation despite an unchanged density. Treatment of hamsters with propranolol resulted in increased density of beta1-adrenoceptors in both strains, but had no effect on their functional efficacy. Moreover, beta2-adrenergic stimulation of adenylyl cyclase was even reduced in propranolol-treated animals, which could not be explained by changes in cardiac G-protein content. 4. Cardiomyopathic BIO TO2 hamsters showed functional uncoupling of cardiac beta1-adrenoceptors, which could not be normalized by propranolol and, therefore, is unlikely to be solely due to agonist-dependent desensitization. The paradoxical reduction in beta2-adrenergic efficiency in propranolol-treated myopathic and control hamsters deserves further investigation.

Adenylyl Cyclases↗
PubMed1999

Effects of propranolol treatment on left ventricular function and intracellular calcium regulation in rats with postinfarction heart failure.

1. Chronic treatment with beta-adrenergic blocking agents can improve survival in patients with heart failure. The mechanisms underlying the beneficial effects and whether these effects are generalizable to ischaemic heart failure are unresolved. 2. We performed echocardiographic-Doppler examinations in rats (n=28) 1 and 6 weeks after myocardial infarction (MI) or sham surgery. Rats were randomized to no treatment or propranolol (500 mg/l in drinking water) after the first echocardiogram. Isometric contractions and intracellular Ca transients were recorded simultaneously in noninfarcted left ventricular (LV) papillary muscles. 3. Untreated MI rats had significant LV dilatation (10.6+/-0.4* vs 8.9+/(-0.3) mm, MI vs control), impaired systolic function (fractional shortening=11+/-2* vs 38+/-2%), and a restrictive LV diastolic filling pattern. MI rats receiving propranolol had similar LV chamber sizes (10.6+/(-0.5) mm) and systolic function (13+/(-2%). The propranolol treated animals had higher LV end-diastolic pressures (27+/-2* vs 20+/(-3 mmHg) and a more restricted LV diastolic filling pattern (increased ratio of early to late filling velocities and more rapid E wave deceleration rate). Contractility of papillary muscles from untreated MI rats was depressed (1.6+/(-0.3) vs 2.4+/(0.5 g mm(-2). In addition, Ca transients were prolonged and the inotropic response to isoproterenol was blunted. Propranolol treatment did not improve force development (1.6+/(-0.3 g mm(-2) or the duration of Ca transients during isoproterenol stimulation. 4. Chronic propranolol treatment in rats with postinfarction heart failure did not improve LV remodeling or systolic function. LV diastolic pressures and filling patterns were worsened by propranolol. Treatment also did not produce appreciable improvement in contractility, intracellular Ca regulation or beta-adrenergic responsiveness in the noninfarcted myocardium.

Adrenergic beta-Antagonists↗
PubMed1975

Hypotensive and renin-suppressing activities of propranolol in hypertensive patients.

1. In patients with mild or moderate essential hypertension, oral propranolol, given in incremental doses, produced a moderate but significant lowering of blood pressure which was correlated with the concentration of propranolol in plasma. 2. Propranolol also reduced plasma renin activity (PRA) in the supine posture, on standing and after intravenous frusemide. However, 'supine' and 'frusemide' PRA values were markedly reduced at a plasma concentration of propranolol that had little effect on blood pressure. 3. On administration of propranolol there was little correlation between blood pressure decrease and PRA suppression, and even less between pretreatment PRA values and hypotensive response. 4. It is concluded that in patients with mild and moderate hypertension and low or normal plasma renin activity, suppression of PRA is not an important determinant of the hypotensive response to propranolol.

Administration, Oral↗
PubMed1982

Effect of propranolol on hepatic blood flow in normal and portal hypertensive rats.

1. The effects of propranolol on heart rate, arterial pressure, portal venous pressure and fractional hepatic blood flow were studied in rats with hepatic artery ligature or with portal vein stenosis, and in sham-operated rats. The effect of propranolol on cardiac output was also studied in normal rats. 2. In rats with hepatic artery ligature or with portal vein stenosis, and in sham-operated rats, propranolol decreased heart rate and portal venous pressure significantly and did not alter arterial pressure. Propranolol decreased fractional hepatic blood flow significantly in rats with hepatic artery ligature, but did not change hepatic blood flow in rats with portal vein stenosis or in sham-operated rats. 3. We conclude therefore that: (a) propranolol decreases portal venous pressure in rats; (b) this decrease in portal venous pressure results in a reduction in portal blood flow which is related, in part, to a reduction in cardiac output; (c) propranolol does not alter hepatic blood flow in normal rats or in rats with portal hypertension.

Animals↗
PubMed1985

Effects of atelectasis and vascular occlusion on the simultaneous measurement of serotonin and propranolol pulmonary extraction in dogs.

To test the relative sensitivity of serotonin and propranolol pulmonary extraction measurements to changes in pulmonary vascular surface, we sequentially subjected anaesthetized dogs to left upper lobe atelectasis, left lung atelectasis and left pulmonary artery occlusion. We used a triple-indicator dilution technique to simultaneously measure the pulmonary extraction of serotonin and propranolol. After an initial series of measurements, dogs received dopamine and dextran to slightly increase pulmonary artery pressure and prevent further recruitment of capillaries. Left upper lobe atelectasis did not modify the pulmonary extraction of serotonin and propranolol. Left lung atelectasis provoked a reduction in the serotonin extraction ratio by only 4%, whereas the propranolol extraction ratio decreased by 13%. After left pulmonary artery occlusion, propranolol and serotonin extraction ratios decreased by 16% and 5% respectively. We conclude that the pulmonary extraction of propranolol is more sensitive to a decrease in pulmonary vascular surface than that of serotonin.

Animals↗
PubMed2006

Failure of propranolol to prevent tilt-evoked systemic vasodilatation, adrenaline release and neurocardiogenic syncope.

In patients with neurocardiogenic syncope, head-up tilt often evokes acute loss of consciousness accompanied by vasodilatation, increased plasma adrenaline and systemic hypotension. Since hypotension increases adrenaline levels and adrenaline can produce skeletal muscle vasodilatation by activating beta2 receptors, adrenaline might induce a positive feedback loop precipitating circulatory collapse. We hypothesized that propranolol, a non-selective beta-blocker, would prevent adrenaline-induced vasodilatation and thereby prevent syncope. Eight subjects with recurrent neurocardiogenic syncope and previously documented tilt-induced syncope with elevated plasma adrenaline levels participated in the present study. Subjects underwent tilt table testing after receiving oral propranolol or placebo in a double-blind randomized crossover fashion. Haemodynamic and neurochemical variables were measured using intra-arterial monitoring, impedance cardiography, arterial blood sampling and tracer kinetics of simultaneously infused [3H]noradrenaline and [3H]adrenaline. The occurrence of tilt-induced neurally mediated hypotension and syncope, duration of tilt tolerance, extent of the decrease in SVRI (systemic vascular resistance index) and magnitude of plasma adrenaline increases did not differ between the propranolol and placebo treatment phases. SVRI was inversely associated with fractional increase in plasma adrenaline during both phases. One subject did not faint when on propranolol; this subject's response is discussed in the context of central effects of propranolol. In this small, but tightly controlled, study, propranolol did not prevent tilt-induced vasodilatation, syncope or elevated plasma adrenaline.

Adolescent↗
PubMed2003

Effect of propranolol and depot lanreotide SR on postprandial and circadian portal haemodynamics in cirrhosis.

BACKGROUND: Long-acting somatostatin analogues have been suggested as an alternative to propranolol for the prevention of variceal rebleeding. AIM: To compare the effectiveness of lanreotide SR, a new depot formulation injected once-weekly, and propranolol in reducing circadian portal blood flow (PVF) and meal-stimulated hepatic venous pressure gradient (HVPG) in patients with liver cirrhosis. METHODS: Patients were randomized to receive either lanreotide SR intramuscularly (30 mg once weekly, n=12) or propranolol (n=12) orally. Hemodynamic measurements were performed on day 0 and on day 21 after a 3-week period of drug administration, while patients received three standard oral liquid test meals. On each study day 27 PVF measurements were performed over 24 h and eight measurements of HVPG during the first postprandial period. RESULTS: Propranolol was more effective than lanreotide SR in reducing baseline HVPG (-21.9 vs. -13.6%, P=0.04) and meal-stimulated HVPG (-16.6 vs. -3.8%, P=0.04). Propranolol reduced circadian PVF significantly by 9.3% (P=0.03) but not lanreotide SR. CONCLUSIONS: Long-term treatment with propranolol reduced baseline and postprandial HVPG and circadian PVF, while lanreotide SR did not. The results of our study do not encourage clinical testing of lanreotide SR 30 mg for the prevention of variceal haemorrhage.

Antihypertensive Agents↗
PubMed1996

Haemodynamic effects of molsidomine and propranolol in patients with cirrhosis.

Propranolol and molsidomine have both been shown to decrease the hepatic venous pressure gradient in patients with cirrhosis. The present study aimed at assessing the effects of the combination of these two drugs on splanchnic and systemic haemodynamics of cirrhotic patients. Fifteen patients with biopsy proven alcoholic cirrhosis had haemodynamic measurements under basal conditions, 60 min after oral administration of 4 mg molsidomine then 15 min after intravenous administration of 15 mg propranolol. As compared with baseline values, molsidomine was found to decrease mean arterial pressure (-7.9%, (P < 0.01), cardiac output (-7.3%, P < 0.01), pulmonary wedged pressure (-45.8%, (P < 0.05) and hepatic venous pressure gradient (-11.7%, P < 0.01). Propranolol decreased heart rate (-21%, P < 0.01), further decreased cardiac output (-20.6%, (P < 0.01) and hepatic venous pressure gradient (-10.5%, P < 0.01). As a whole, molsidomine plus propranolol decreased mean arterial pressure (-8%, P < 0.01), heart rate (-19%, P < 0.01), cardiac output (-26.5%, P < 0.01) and hepatic venous pressure gradient (-21%, P < 0.01). Pulmonary wedged pressure, liver blood flow and hepatic intrinsic clearance of indocyanine green were not significantly changed by the association of molsidomine and propranolol. We conclude that in patients with cirrhosis, molsidomine and propranolol potentiate their effects on hepatic venous pressure gradient. Such a combination could therefore prove useful in the treatment of portal hypertension.

Adrenergic beta-Antagonists↗
PubMed1999

Reversal of propranolol blockade of adrenergic receptors and related toxicity with drugs that increase cyclic AMP.

An overdose of propranolol, a widely used nonselective beta-adrenergic receptor blocking agent, can result in hypotension and bradycardia leading to irreversible shock and death. In addition, the blockade of adrenergic receptors can lead to alterations in neurotransmitter receptors resulting in the interruption of the activity of other second messengers and the ultimate cellular responses. In the present experiment, three agents, aminophylline, amrinone, and forskolin were tested in an attempt to reverse the potential lethal effects of a propranolol overdose in dogs. Twenty-two anesthetized beagle dogs were given a 10-min infusion of propranolol at a dose of 1 mg/kg/min. Six of the dogs, treated only with intravenous saline, served as controls. Within 15-30 min all six control dogs exhibited profound hypotension and severe bradycardia that led to cardiogenic shock and death. Seven dogs were treated with intravenous aminophylline 20 mg/kg 5 min after the end of the propranolol infusion. Within 10-15 min heart rate and systemic arterial blood pressure returned to near control levels, and all seven dogs survived. Intravenous amrinone (2-3 mg/kg) given to five dogs, and forskolin (1-2 mg/kg) given to four dogs, also increased heart rate and systemic arterial blood pressure but the recovery of these parameters was appreciably slower than that seen with aminophylline. All of these animals also survived with no apparent adverse effects. Histopathologic evaluation of the hearts of the dogs treated with aminophylline showed less damage (vacuolization, inflammation, hemorrhage) than the hearts from animals given propranolol alone. Results of this study showed that these three drugs, all of which increase cyclic AMP, are capable of reversing the otherwise lethal effects of a propranolol overdose in dogs.

Adenylyl Cyclases↗