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PubMed1999

Carvedilol, a new nonselective beta-blocker with intrinsic anti- Alpha1-adrenergic activity, has a greater portal hypotensive effect than propranolol in patients with cirrhosis.

Only some patients show a substantial hepatic venous pressure gradient (HVPG) reduction after propranolol, which makes it desirable to investigate drugs with greater portal hypotensive effect. The aim of this study was to investigate whether carvedilol, a nonselective beta-blocker with anti-alpha1-adrenergic activity, may cause a greater HVPG reduction than propranolol. Thirty-five cirrhotic patients had hemodynamic measurements before and after the random administration of carvedilol (n = 14), propranolol (n = 14), or placebo (n = 7). Carvedilol markedly reduced HVPG, from 19.5 +/- 1.3 to 15.4 +/- 1 mm Hg (P <.0001). This HVPG reduction was greater than after propranolol (-20.4 +/- 2 vs. -12.7 +/- 2%, P <.05). Moreover, carvedilol decreased HVPG greater than 20% of baseline values or to </=12 mm Hg in a greater proportion of patients (64% vs. 14%, P <.05). Both drugs caused similar reductions in hepatic and azygos blood flows, suggesting that the greater HVPG decrease by carvedilol was because of reduced hepatic and portocollateral resistance. Propranolol caused greater reductions in heart rate and cardiac output than carvedilol, whereas carvedilol caused a greater decrease in mean arterial pressure (-23.1 vs. -11%, P <.05). Thus, carvedilol has a greater portal hypotensive effect than propranolol in patients with cirrhosis, suggesting a greater therapeutic potential. However, it causes arterial hypotension, which calls for careful evaluation before its long-term use.

Adrenergic alpha-Antagonists↗
PubMed1985

Comparison of acebutolol and propranolol therapy for ventricular arrhythmias.

The effects of acebutolol, a new investigational cardioselective beta blocker, and propranolol on ventricular arrhythmias were compared in 14 patients with more than 30 premature ventricular contractions (PVCs) per hour. Each patient served as their own control, receiving both drugs and placebo in random sequence and in double-blind fashion, with an intervening one-week, drug-free period. Each drug was given for a two-month period, the maximum acebutolol dosage reaching 600 mg tid and the maximum propranolol dosage 80 mg tid. Seventy-two-hour ambulatory electrocardiographic monitoring assessed arrhythmia frequency for each study period. Mean PVC counts did not significantly differ during the two control periods. Acebutolol decreased mean PVC count by 65% (P less than .02), with eight patients exhibiting a 70% or greater decrease. Only three patients exhibited a similar decline with propranolol. The incidence of PVCs was not significantly decreased by propranolol. Acebutolol reduced the number of couplets by 70% (P less than .04), whereas propranolol did not significantly affect couplets. At the dosage of 600 mg tid, acebutolol was well tolerated, effectively suppressed total PVCs and couplets, and appeared to be more effective than propranolol administered at 80 mg tid.

Acebutolol↗
PubMed1987

Pharmacokinetics and pharmacodynamics of long-acting propranolol 60-mg capsules: a comparative evaluation.

This double-blind, placebo-controlled, four-period cross-over study was undertaken to evaluate the sustained-release characteristics of long-acting propranolol hydrochloride (Inderal LA, Ayerst Laboratories, New York, NY) 60 mg qd, to compare the pharmacokinetic and pharmacodynamic properties of this formulation with conventional propranolol 20 mg tid, and to evaluate the proportionality of long-acting propranolol 60 mg (LA 60 mg) and long-acting propranolol 80 mg (LA 80 mg). Pharmacodynamic effects were evaluated in 34 healthy subjects by assessing heart rate, systolic blood pressure, and the product of heart rate and systolic blood pressure (double product) after exercise-induced tachycardia following both acute (day 1) and steady state (day 4) drug administration. The Cmax following administration of LA 60 mg was 9.5 and 11.4 ng/mL on days 1 and 4, respectively, compared with 18.8 and 20.0 ng/mL with 20 mg tid (P less than .0001). The tmax for LA 60 mg was significantly later (P less than .0001) than for conventional propranolol. Additionally, the apparent plasma half-life was significantly longer (P less than .0001) than with conventional propranolol. The LA 60-mg formulation was dose proportional to the LA 80-mg formulation. Pharmacodynamic evaluations showed no significant differences between LA 60 mg and 20 mg tid at any times tested with either acute or steady state dosing. This study demonstrates that LA 60 mg displays characteristics of a sustained-release formulation, is proportional with LA 80 mg, and produces pharmacodynamic effects that are similar to 20-mg tid dosing.

Administration, Oral↗
PubMed1989

Blood pressure and blood pressure variability following withdrawal of propranolol and clonidine.

The effects of placebo, propranolol, and clonidine on blood pressure and blood pressure variability were examined in 14 subjects who had moderate essential hypertension. Hydrochlorothiazide was given throughout successive 4- to 5-week periods of placebo, propranolol, and clonidine administration. During each treatment period, subjects were admitted twice to the clinical research unit for 24-hour blood pressure monitoring performed during administration of placebo, propranolol and clonidine and repeated 1 to 2 weeks later during the first 24 hours after the abrupt cessation of placebo or drug administration. Blood pressure was recorded at 15-minute intervals using an automated noninvasive recorder (Arteriosonde, Roche, New Jersey). Systolic and diastolic blood pressure readings were averaged and the standard deviation taken as the measure of long-term variability (LTV). Systolic and diastolic blood pressure in sequential overlapping blocks of seven readings were averaged and the standard deviation calculated. Short-term variability (STV) was estimated as the average of the standard deviations of the running means. During placebo administration and withdrawal, systolic and diastolic blood pressures as well as LTV and STV were unchanged. Systolic and diastolic pressures did not differ during propranolol administration from those during propranolol withdrawal or placebo withdrawal. Systolic and diastolic LTV and STV did not differ during propranolol administration and withdrawal from those observed during placebo administration or withdrawal. After clonidine withdrawal, both systolic and diastolic pressures increased to values significantly greater than during clonidine administration. These values were significantly greater than those observed after placebo withdrawal, thereby indicating rebound hypertension. After clonidine withdrawal, seven of fourteen subjects developed systolic pressure rebound; diastolic pressure rebound was observed in three patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Effect of the sialylation state of alpha 1-acid glycoprotein on propranolol binding.

alpha 1-Acid glycoprotein (AAG) exists in a variety of sialylated states which can be influenced by certain disease states. The purpose of the present study was to establish the effect of the sialylation state of AAG on the binding of a model cationic drug (propranolol). Extensive in vitro enzymatic desialylation of isolated human AAG was achieved utilizing neuraminidase bonded to agarose beads. Propranolol binding to native and desialylated AAG was determined by equilibrium dialysis. Desialylated AAG exhibited a modest increase in propranolol free fraction due to a decrease in the affinity constant (Ka) compared to untreated AAG (3.3 X 10(5) M-1 versus 4.0 X 10(5) M-1, respectively). A modest 15% increase was predicted for the free fraction of propranolol in serum containing desialylated AAG at therapeutic propranolol concentrations (less than 0.1 microgram/ml). Therefore, the clinical significance of desialylated AAG appears to be minor with respect to propranolol binding.

Dialysis↗
PubMed1990

Bioavailability of propranolol following oral and transdermal administration in rabbits.

The systemic bioavailability of propranolol was evaluated following oral and transdermal administration in rabbits. Using a four-way crossover study, the bioavailability of propranolol following oral administration was determined to be 12.3 +/- 5.9%, indicating that propranolol is subject to extensive hepatic first-pass metabolism in rabbits. Transdermal delivery of propranolol, via an adhesive delivery device, resulted in a bioavailability of 74.8 +/- 10.1%, indicating that the transdermal delivery of propranolol can significantly increase systemic bioavailability over oral administration. Skin irritation studies indicated that neither propranolol nor the adhesive used in the device caused any appreciable skin irritation.

Administration, Cutaneous↗
PubMed1991

Enhancement of propranolol hydrochloride and diazepam skin absorption in vitro: effect of enhancer lipophilicity.

The enhancement of model hydrophilic (propranolol hydrochloride) and lipophilic (diazepam) drug penetration across rat and hairless mouse skin in vitro has been studied. Preliminary experiments established that most n-alkanes having chain lengths of between 7 and 16 promote the flux of both drugs. For propranolol, enhancement varied parabolically with carbon number; for diazepam, heptane was ineffective and all others were essentially equipotent. Enhancement by n-nonane was then compared with that by n-nonanol. Propranolol flux was increased by both enhancers, whereas diazepam penetration was not affected by the less lipophilic alcohol. The enhancement of propranolol by n-nonane and n-nonanol was examined as a function of adjuvant concentration in the applied formulation. Maximum increases in maximum penetration rates of 6.5-fold (n-nonane) and 8.2-fold (n-nonanol) were determined. As expected, the enhancement was saturable, indicative of a maximally perturbed stratum corneum. Finally, the penetration enhancing abilities of six monoterpenes were assessed. The purely hydrocarbon analogues promoted both propranolol and diazepam transport to an extent similar to that of n-nonane. The terpenes with hydrogen-bonding ability, however, only enhanced propranolol flux (at a level comparable to n-nonanol). While the data reported do not directly reveal mechanistic information on percutaneous penetration enhancement, they do provide a starting point for the rational investigation of interrelationships between drug, enhancer, and skin. Such information is clearly essential for the optimization and exploitation of transdermal drug delivery.

Alkanes↗
PubMed1993

Inefficacy of propranolol in attenuation of drug-induced parkinsonian tremor.

We investigated the tremolytic effect of long-acting propranolol (propranolol-LA) in six subjects with drug-induced parkinsonism (DIP), using a double-blind, placebo-controlled, crossover experimental design. Subjects received propranolol-LA for 2 weeks and placebo for 2 weeks, with no change in neuroleptic treatment. Tremor frequency and amplitude were objectively quantified at the end of each 2-week period by computerized tremorgram recording. There were no significant differences in attenuation of DIP tremor by propranolol-LA and placebo. Previous investigations reported in the literature have found propranolol to attenuate the tremor of idiopathic parkinsonism (IPD). It is expected that DIP and IPD tremor would respond similarly to propranolol if a solely peripheral or spinal cord tremolytic action were operative. A possible differential attenuation of IPD tremor and DIP tremor provides support for the concept of a higher central tremolytic mechanism of beta-adrenergic receptor-blocking drugs.

Aged↗
PubMed1999

Chronic administration of propranolol impairs inhibitory avoidance retention in mice.

Adrenergic systems are importantly involved in memory storage processes. As such, agents that alter adrenergic receptors, such as "beta-blockers," also alter memory storage. However, the anxiety literature cautions that beta-adrenergic receptor antagonists, such as propranolol, may have different behavioral effects with acute vs chronic dosing. The effects of chronic propranolol specifically on memory modulation are unknown. This study was designed to evaluate the effects of chronic propranolol on retention for an aversive task, in which there is endogenous adrenergic activation. Adult male ICR mice were given daily injections of one of four doses of propranolol (2, 4, 8, and 12 mg/kg) or 0.9% NaCl vehicle for 15 days prior to, and continuing during, behavioral tests of exploration and retention. Exploratory behavior, as an index of anxiety level, was measured in a conventional elevated plus-maze, whereas retention of an aversive experience was measured in a step-through inhibitory avoidance apparatus. Sensitivity to aversive footshock was also evaluated. Compared to controls, propranolol-treated mice showed a dose-dependent decrease in retention for the inhibitory avoidance task, but no effect on anxiety on the plus-maze or on footshock sensitivity. Taken together with results from previous studies, it is apparent that propranolol can have different behavioral effects when administered acutely vs chronically, and its chronic effects significantly impair memory storage processes. Since these drugs are typically used chronically, and often in older adults, they could contribute to functional memory impairments.

Adrenergic beta-Antagonists↗
PubMed2000

Chronic propranolol induces deficits in retention but not acquisition performance in the water maze in mice.

Agents that alter adrenergic receptors, such as "beta-blockers," also alter memory storage. However, reports suggest that beta-adrenergic receptor antagonists, such as propranolol, have conflicting behavioral effects with acute vs chronic dosing. This study was designed to evaluate the effects of chronic propranolol on retention for a spatial learning task. Adult male ICR mice were given daily injections of propranolol (2, 4, 8, or 12 mg/kg ip) or 0. 9% NaCl for 15 days prior to, and during, trials in a Morris water maze. Mice received five massed acquisition (escape) trials in each of three daily sessions, followed by a single 60-s probe trial on the fourth day. The location of the submerged platform was constant for each animal over acquisition trials, but varied across animals; starting position varied across trials. A 5 (dose) x 3 (trial blocks) mixed factorial ANOVA for escape time yielded a significant trial blocks effect only (p <.001), showing performance improving over sessions. Time spent in the target quadrant on the probe trial was shorter under all doses of propranolol when compared to vehicle group (all p <.001), indicating poorer retention of prior platform location. This effect, however, was not dose-related. Swim speed was not significantly affected by propranolol. These data demonstrate that chronic dosing with propranolol can impair retention of spatial learning, which cannot be attributed to reduced arousal or motor function.

Adrenergic beta-Antagonists↗
PubMed1998

Effect of propranolol and nifedipine on maximal electroshock-induced seizures in mice: individually and in combination.

A comparative effect of propranolol and nifedipine administered individually and in combination at graded dose levels; and that of phenytoin at 30 mg kg-1 on maximal electroshock (MES)-induced seizure in mice was investigated. Propranolol in doses of 10 mg kg-1 and 20 mg kg-1, and nifedipine in doses of 8 mg kg-1 and 16 mg kg-1 significantly modified MES activity. Propranolol (40 mg kg-1), and a combination of propranolol (20 mg kg-1) and nifedipine (8 mg kg-1), produced antiMES activity, which was comparable to that of phenytoin (30 mg kg-1). In mice treated with propranolol and nifedipine combination, the tonic flexor and tonic extensor phase ratios (F/E ratio) were significantly higher than individual drug responses. Our findings suggest that a combination of propranolol and nifedipine has either synergistic or an additive effect in controlling MES-induced seizures in mice.

Animals↗
PubMed1986

The distribution of (-)-propranolol in the isolated rabbit iris.

It has been postulated that propranolol lowers the intraocular pressure by adrenergic neurone block. However, in the isolated iris of albino rabbits, there was only a small degree of cocaine-sensitive (i.e., neuronal) accumulation of 3H-(-)-propranolol, and none at all after pretreatment of the animals with reserpine. Moreover, after preloading of the iris with 3H-(-)-propranolol, veratridine failed to release any labelled material. Hence, any adrenergic neurone blocking action of propranolol is highly unlikely. Albino and pigmented irides were first exposed to 3H-(-)-propranolol and then washed out. The results and their compartmental analysis indicated an extensive binding of 3H-(-)-propranolol in or at pigment cells; the binding is characterized by a low dissociation constant. It is very likely that the initial binding and the subsequent slow dissociation from pigment cells explains the long duration of action of beta-adrenoceptor antagonists in human therapy.

Albinism↗
PubMed1993

Effect of propranolol on portal vein hemodynamics: assessment by duplex sonography and indocyanine green clearance in healthy volunteers.

In the past decade several randomized trials have shown a beneficial effect of propranolol in cirrhotic patients. The effect of propranolol has been attributed to a reduction in portal vein pressure. So far the monitoring of portal vein hemodynamics following propranolol administration has been achieved mainly by hepatic vein catheterization. We studied the effect of propranolol on portal vein hemodynamics noninvasively in five healthy volunteers using duplex sonography and indocyanine green clearance. Measured by duplex sonography, blood flow was reduced by 28.6% in the portal vein (P < 0.05) and by 8.7% in the hepatic artery (NS) 60 min after oral administration of 80 mg propranolol. During this time total hepatic blood flow, measured by indocyanine green clearance, was reduced by 19.5% (P < 0.05). We conclude that both methods are useful for the study of portal vein hemodynamics during propranolol therapy, duplex sonography being more easily practicable.

Adult↗
PubMed1993

Lack of influence of short-term treatment with propranolol and terbutaline on metabolism and energy expenditure of the Na-K pump in human erythrocytes evaluated by microcalorimetry.

A double blind placebo-controlled study was conducted of the effects of oral propranolol (beta 1 beta 2-adrenoceptor antagonist) and terbutaline (beta 2-adrenoceptor agonist) on erythrocyte heat production, measured by direct microcalorimetry under static conditions at 37 degrees C and pH 7.4. Propranolol 80 mg and terbutaline slow-release 7.5 mg were randomly administered twice daily for one week to 15 healthy males, using a cross-over design. No thermogenic difference was detected. Serum potassium was significantly decreased by terbutaline but was only slightly increased by propranolol, but no relationship was found between changes in the extra- and intracellular levels. In the placebo group, 10% of total cell energy was consumed by the Na-K pump, as assessed by ouabain inhibition, and this value was not significantly affected by the treatments. Thus, it seems unlikely that there is a clinically relevant influence on the Na-K pump in erythrocytes during continuous terbutaline or propranolol medication. It is concluded that short term medication with propranolol and terbutaline in therapeutic doses has almost no thermal or metabolic effect on human erythrocytes. The results indirectly imply that no clinically relevant beta-adrenoceptor effects are mediated in erythrocytes and this may also be true with regard to the 'membrane effect' of propranolol.

2,3-Diphosphoglycerate↗
PubMed1979

Action of d-propranolol in manic psychoses.

Six manic patients were treated with high doses of d-propranolol or d- and dl-propranolol in a double-blind, placebo controlled study. The following variables were measured: propranolol dosage, propranolol serum concentration, pulse frequency, blood pressure, and psychotic behavior. In all cases an improvement was noticed. High dosages were necessary to obtain sufficient effect. The antimanic property of d-propranolol was approximately 50% smaller than the antimanic property of dl-propranolol. We conclude that at least some part of the antimanic action of beta-blockers is independent from the beta-blocking property.

Adult↗
PubMed1979

The effect of propranolol treatment in shizophrenia on CSF amine metabolites and prolactin.

Recent reports have suggested that high doses of propranolol may be an effective treatment in schizophrenia. To determine whether such treatment has effects on cerebrospinal fluid (CSF) amine metabolites and prolactin similar to the effects of the neuroleptic drugs, we studied CSF from ten patients before and after propanolol therapy. The initial CSF sample was removed after a drug-free period and propranolol dosage was then increased over 1 week to 1000 mg daily in all ten patients. A second CSF sample was removed after 3 weeks of propranolol therapy. Propranolol levels and prolactin in CSF were measured by radioimmunoassay. Homovanillic acid, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenylethylene glycol were measured by gas chromatography-mass spectrometry. Propranolol had no effect on the prolactin or amine metabolite concentrations. CSF propranolol levels averaged 40 ng/ml (range less than 1--78).

Adult↗
PubMed1987

The effect of propranolol on exercise induced tachycardia is determined by plasma concentration and the density of adrenergic receptors on leukocytes.

The chronotropic response to a single oral dose of propranolol in 23 healthy subjects has been related to the plasma propranolol concentration and the density of beta-adrenoceptors on peripheral polymorphonuclear leucocytes. The percentage reduction in exercise-induced tachycardia was significantly correlated with the log plasma propranolol concentration within subjects but not between subjects. Taking the concentration of the active metabolite 4-hydroxypropranolol into account did not improve the interindividual correlation. The reduction in exercise-induced tachycardia was significantly correlated with the maximum binding density of (125I)-hydroxybenzylpindolol on polymorphonuclear leucocyte membrane fragments measured before medication. A response index (% reduction in exercise-induced tachycardia/plasma propranolol concentration) was correlated with the maximum binding density of (125I)-hydroxybenzylpindolol (pre-drug) at 2 h (rs = 0.72), 4 h (rs = 0.84) and 6 h (rs = 0.73) after dosing. The data suggest that interindividual variation in the response to propranolol after a single oral dose is determined by interindividual differences both in plasma propranolol and adrenoceptor density.

Adult↗
PubMed1987

Comparison of nicardipine and propranolol in the treatment of mild and moderate hypertension.

In a double-blind controlled trial 22 patients with mild or moderate essential hypertension were treated with nicardipine 30 mg t.d.s. and 19 patients with propranolol 80 mg t.d.s. as monotherapy for 24 weeks. Blood pressure in both groups at the end of trial was equally and significantly reduced; systolic pressure 22.2 mmHg and diastolic pressure 15.5 mmHg in the supine position, and 24.4 mmHg and 18.4 mmHg, respectively, in the standing position in those on nicardipine, and by 23.7 and 16.2 mmHg and 28.0 and 19.2 mmHg, respectively, in the propranolol group. There was an initial increase in heart rate in the nicardipine group, but the rise was only moderate (3 beats/min supine p = 0.3219, and 7 beats/min standing, p = 0.0203) at the end of the 24 weeks. In the propranolol group heart rate was reduced markedly. Adverse effects occurred in 77% of patients on nicardipine and in 63% of those on propranolol, and there were no unexpected findings. The effects were mild in both groups and did not lead any patient to stop medication. One patient on propranolol was withdrawn from the trial because of poor blood pressure control and suspected angina pectoris after 5 weeks on active medication. There were no significant changes in blood chemistry, including lipoprotein classes. Overall, in comparison with propranolol, nicardipine was effective, well-tolerated and safe to use in the monotherapy of mild or moderate essential hypertension.

Adult↗