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PubMed1989

Effect of turpentine-induced inflammation on the disposition kinetics of propranolol, metoprolol, and antipyrine in the rat.

Plasma concentrations after oral administration of the high extraction drug propranolol are increased in patients and animals with inflammation. This could be due to increased serum propranolol binding, but also to decreased first-pass metabolism. We studied the pharmacokinetics of 3 drugs in control rats and in rats with turpentine-induced inflammation: propranolol, which is bound extensively to alpha 1-acid glycoprotein (alpha 1-AGP); metoprolol, another high extraction drug, but which is negligibly bound to alpha 1-AGP; and antipyrine, a low extraction drug, not bound to serum proteins. After IV administration of propranolol in rats with inflammation, systemic clearance, volume of distribution, and free fraction decreased, and the area under the curve (AUC) increased, whereas the half-life did not change. As the systemic clearance of a high extraction drug such as propranolol depends on hepatic blood flow only, a fall in hepatic blood flow or transition to a low extraction situation should be postulated. After oral administration of propranolol, the AUC was increased 20-fold in rats with inflammation; as the decrease in free fraction was only 4-fold, it can be concluded that a considerable decrease in hepatic intrinsic clearance was present. For metoprolol, in contrast to propranolol, after IV administration, no changes in pharmacokinetic parameters as a result of inflammation were observed. After oral administration, the AUC was increased about 4 times in rats with inflammation; as metoprolol is only negligibly bound to serum proteins, the increase in AUC can be attributed to a decrease in hepatic intrinsic clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1984

Effects of propranolol and exercise on cardiac dynamics and organ blood flow distribution in dogs.

The additive effects of propranolol and exercise on peripheral blood flow distribution were studied in conscious dogs. During treadmill exercise (8-10 km/h and 0% grade for 15 min.) cardiac performance increased significantly in parallel with myocardial and muscular blood flow (greater than 100%). Blood perfusion to liver and spleen decreased significantly (30% and 34%) while blood flow to other organs was unaltered. Under resting conditions propranolol only modified blood flow to liver and spleen (-50% and -38%). During exercise after propranolol a limited augmentation in cardiac performance and in myocardial and muscular blood flow was observed; splanchnic blood flow which was most affected by propranolol at rest did not further decrease during exercise after propranolol. The present observations demonstrate that propranolol, despite minor haemodynamic modifications, induces significant alterations in blood flow to splanchnic organs. The influence of beta-adrenoreceptor blockade was even more evident under conditions of augmented sympathetic activity as reflected by a significant limitation of increase in cardiac performance, myocardial and muscular blood flow and by a sustained redistribution of splanchnic blood flow during exercise after propranolol.

Animals↗
PubMed1981

Effect of intracisternal 5,-7-dihydroxytryptamine on the acute antihypertensive action of propranolol in the sino-aortic denervated anaesthetized dog.

1 The anti-hypertensive effects of intravenously and intracisternally administered (+/-)-propranolol were studied in anaesthetized dogs with acute neurogenic (sino-aortic denervation) hypertension. The animals were pretreated 7 days earlier with intracisternally administered 5,7-dihydroxytryptamine (5,7-DHT 200 microgram/kg plus desipramine 5 mg/kg i.v.). 2 5,7-DHT (plus desipramine) failed to decrease both basic blood pressure and heart rate measured before sino-aortic denervation. After 5,7-DHT (plus desipramine) pretreatment, acute sino-aortic denervation induced a rise in blood pressure and stimulated the heart rate, these effects being similar (in intensity and duration) to those observed in control (saline-pre-treated) debuffered dogs during the first hour following the deafferentation. 3 In debuffered dogs, (+/-)-propranolol given by intracisternal (50 microgram/kg) or intravenous (300 microgram/kg) routes decreased both blood pressure and heart rate. 4 5,-DHT (plus desipramine) pretreatment abolished the antihypertensive effect of intracisternal propranolol whereas the action of intravenous propranolol was only delayed. In contrast, this pretreatment failed to reduce and even sometimes enhanced the negative chronotropic response induced by propranolol. 5 These results suggest that central 5-hydroxytryptaminergic pathways play an important role in the acute hypotension elicited by intracisternal (+/-)-propranolol in debuffered hypertensive anaesthetized dogs, but little, if any in propranolol-induced bradycardia.

5,7-Dihydroxytryptamine↗
PubMed1983

Inhibition by propranolol of the contractile response of the rat diaphragm to tetanic field stimulation in vitro.

Contraction of the rat isolated diaphragm in response to maximal tetanic stimulation was examined before and after isoprenaline or propranolol. Isoprenaline (10(-4)M) did not affect maximum isometric force, whereas propranolol depressed maximum force in a concentration-dependent manner (10(-6)-10(-4)M). Inhibition due to propranolol (10(-4)M) could not be overcome by increasing the intensity or duration of electrical stimulation, and was only partially reversed (mean 73% +/- 10 s.e. mean) after washing. Pretreatment with isoprenaline did not alter the response of the muscle to propranolol, nor did neuromuscular blockade with (+)-tubocurarine. The response to either stereoisomer of propranolol was similar to that obtained with the racemate. Atenolol, a beta-adrenoceptor blocking agent without membrane stabilizing activity, had minimal (less than 10%) depressant effects on diaphragmatic force development. Lignocaine (8.5 X 10(-6)-8.5 X 10(-5)M) produced a concentration-related decrease in isometric force, similar to that with propranolol. It is concluded that propranolol decreases the contractile force of the rat isolated diaphragm by a mechanism related to stabilization of excitable membranes.

Animals↗
PubMed1983

Propranolol-induced airway hyperreactivity in guinea-pigs.

In anaesthetized, spontaneously breathing guinea-pigs, enhanced bronchoconstrictor responses (increases RL) to histamine were measured following intravenous injection of practolol, (+/-)-propranolol, (+)- and (-)-propranolol. Propranolol enhanced not only histamine- but 5-hydroxytryptamine (5-HT)-induced bronchoconstrictions and its effects lasted up to 2 h. This increased airway sensitivity was not due to beta-adrenoceptor blockade because: (a) similar effects were produced by racemic propranolol and its two isomers (+)- and (-)-propranolol and (b) whilst equal doses of (+/-)- and (+)-propranolol produced the same potentiation of histamine bronchoconstriction, only (+/-)-propranolol also caused a measurable beta-adrenoceptor blockade in the airways. The enhanced histamine- and 5-HT-induced bronchoconstrictions were antagonized by the leukotriene antagonist FPL 55712 and by the lipoxygenase/cyclo-oxygenase inhibitor BW755c. The results demonstrate that endogenously released leukotrienes can produce not only a direct bronchospasm but may enhance the effects of other bronchoconstrictor agents. The relevance of this leukotriene-mediated hyperreactivity to the non-specific airway hyperreactivity seen in asthmatics is discussed.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1985

Depolarization-induced release of propranolol and atenolol from rat cortical synaptosomes.

The accumulation and release of [3H]-propranolol and [3H]-atenolol were examined in synaptosomes from rat cerebral cortex. Synaptosomes accumulated 20 pmol propranolol and 0.6 pmol atenolol mg-1 protein when incubated at 30 degrees C with radiolabelled drugs (0.1 microM). Exposure of propranolol-loaded synaptosomes to elevated K+, Rb+ or Cs+ evoked a concentration-dependent increase in propranolol efflux. The action of these ions in releasing propranolol was highly correlated with their ability to produce synaptosomal membrane depolarization, as estimated with the voltage-sensitive dye diS-C3-(5). Elevated K+ also promoted atenolol release from synaptosomes in a concentration-dependent manner. Veratridine (10 microM) released propranolol and atenolol from synaptosomes and these effects were antagonized by tetrodotoxin (1 microM). Under Ca2+-free conditions, K+-induced release of propranolol was reduced by 37% and atenolol release was diminished by 68%. The results support the concept that both polar and non-polar beta-adrenoceptor blocking drugs may be accumulated by nerve endings for release by membrane depolarization and suggest that neural storage and release of these molecules may influence their concentrations at localized sites of action.

Animals↗
PubMed1987

Effect of propranolol on ventricular rate during atrial fibrillation in the Wolff-Parkinson-White syndrome.

Atrial fibrillation was induced during an electrophysiology study in 10 patients with the Wolff-Parkinson-White (WPW) syndrome, after determination of baseline properties of the accessory atrioventricular (AV) connection; intravenous propranolol (0.2 mg/kg) was then administered. Atrial fibrillation terminated during the drug infusion in three patients, allowing determination of propranolol's effects on conduction and refractoriness during sinus rhythm, before atrial fibrillation was reinduced. In these three patients propranolol had no effect on refractoriness or conduction properties of the accessory AV connection during sinus rhythm. The mean ventricular rate during atrial fibrillation was slowed by 15-56 beats/min in six patients, had no effect on the mean rate in three patients, and markedly increased the ventricular rate (203 to 267 beats/min) in one patient. In this patient, 54% of QRS complexes during atrial fibrillation were narrow, compared to 0-25% in the other patients. Propranolol reduced the percentage of QRS complexes that were narrow from 13 +/- 16% to 1 +/- 2% (mean +/- standard deviation, p less than 0.05). We conclude that propranolol may slow the ventricular rate during atrial fibrillation in some patients with the WPW syndrome, probably by blocking the effects of adrenergic activation. However, propranolol should not be used in patients with the WPW syndrome who have atrial fibrillation, if most QRS complexes during atrial fibrillation are preexcited. When a large percentage of QRS complexes are narrow, propranolol may increase the ventricular rate, probably by eliminating concealed retrograde conduction in the accessory AV connection.

Adult↗
PubMed1982

Propranolol and essential tremor: rôle of the membrane effect.

d-propranolol is almost devoid of beta-blocking effect but has the same membrane stabilizing properties as the dl-form. In order to study the importance of membrane stabilizing activity versus beta blockade in the therapeutical effect of propranolol on essential tremor, we compared d-propranolol with dl-propranolol in 24 patients in a placebo-controlled double-blind cross-over study. dl-propranolol reduced tremor intensity better than d-propranolol. The d-form did not significantly differ from placebo in its effects on tremor, although it did reduce the heart rate slightly. It is concluded that the membrane effect is not important in the therapeutic effect of propranolol in essential tremor.

Adult↗
PubMed1993

An in-vitro and in-vivo correlative approach to the evaluation of ester prodrugs to improve oral delivery of propranolol.

A series of ester prodrugs of propranolol was synthesized by incorporating substituents (straight alkyl, branched alkyl, acyloxyalkyl and cycloalkyl) into the beta-hydroxy function of propranolol with the aim of protecting the drug against first-pass metabolism following oral administration. The in-vitro hydrolysis rates of the prodrugs were, in increasing order, liver homogenate >> plasma > buffers. The pH-rate profile of the prodrugs showed maximum stability around pH 4.0; the hydrolysis rates were drastically increased over pH 6.8. QSAR analysis revealed hydrophobic (pi) and electronic (sigma) effects of the substituents play the main roles for prodrug hydrolysis in buffers and plasma, while hydrolysis in liver homogenate could not be well explained by any of these parameters. Four prodrugs (O-acetyl-, O-butyryl-, O-isovaleryl- and O-cyclopropanoyl-propranolol) were selected for oral administration based on their hydrolysis in-vitro. Following oral administration of prodrugs to beagle dogs the absolute bioavailabilities (F) of propranolol were about 2-4-fold that after an equivalent dose of propranolol. The prodrugs were rapidly absorbed and regenerated propranolol to attain peak plasma levels at 0-0.5h. Intact prodrug levels were also observed, which varied depending on their respective stabilities in in-vitro media. A linear relationship between F of propranolol and log P was obtained. F further appeared to be parabolically dependent on the observed hydrolysis rates of prodrugs in liver homogenate suggesting optimal design manipulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1998

A study on the in-vitro percutaneous absorption of propranolol from disperse systems.

Transdermal administration of propranolol can be used to avoid hepatic first-pass metabolism of the drug. The effect of polysorbate 80 concentration on the permeation of propranolol incorporated into micelles of polysorbate 80 in water, oil-in-water microemulsions of isopropyl myristate-polysorbate 80-sorbitol-water and oil-in-water emulsions of isopropyl myristate-polysorbate 80-sorbitan monooleate-water has been investigated by use of an artificial double-layer membrane, composed of a barrier foil and a lipid barrier, in Franz-type diffusion cells. Reversed-phase high-performance liquid chromatography, with celiprolol as internal standard, was used to determine the concentration of propranolol in the receptor compartment and a logarithmic equation was used to estimate the apparent permeability coefficient of propranolol from disperse systems. For each disperse system the apparent permeability coefficient of propranolol decreased with increasing polysorbate 80 concentration. Moreover, for a given polysorbate 80 concentration the apparent permeability coefficient of propranolol increased when the disperse system was changed from emulsion to microemulsion and then to solubilized system, because of the increasing interfacial area of total disperse phase. The results show that transdermal permeation of propranolol is greater when it is diffused from solubilized systems rather than from microemulsions or emulsions.

Administration, Cutaneous↗
PubMed2004

Disposition kinetics of propranolol isomers in the perfused rat liver.

The aim of this study was to define the determinants of the linear hepatic disposition kinetics of propranolol optical isomers using a perfused rat liver. Monensin was used to abolish the lysosomal proton gradient to allow an estimation of propranolol ion trapping by hepatic acidic vesicles. In vitro studies were used for independent estimates of microsomal binding and intrinsic clearance. Hepatic extraction and mean transit time were determined from outflow-concentration profiles using a nonparametric method. Kinetic parameters were derived from a physiologically based pharmacokinetic model. Modeling showed an approximate 34-fold decrease in ion trapping following monensin treatment. The observed model-derived ion trapping was similar to estimated theoretical values. No differences in ion-trapping values was found between R(+)- and S(-)-propranolol. Hepatic propranolol extraction was sensitive to changes in liver perfusate flow, permeability-surface area product, and intrinsic clearance. Ion trapping, microsomal and nonspecific binding, and distribution of unbound propranolol accounted for 47.4, 47.1, and 5.5% of the sequestration of propranolol in the liver, respectively. It is concluded that the physiologically more active S()-propranolol differs from the R(+)-isomer in higher permeability-surface area product, intrinsic clearance, and intracellular binding site values.

Animals↗
PubMed2006

D-propranolol attenuates lysosomal iron accumulation and oxidative injury in endothelial cells.

The influence of selected beta-receptor blockers on iron overload and oxidative stress in endothelial cells (ECs) was assessed. Confluent bovine ECs were loaded with iron dextran (15 muM) for 24 h and then exposed to dihydroxyfumarate (DHF), a source of reactive oxygen species, for up to 2 h. Intracellular oxidant formation, monitored by fluorescence of 2',7'-dichlorofluorescin (DCF; 30 microM), increased and peaked at 30 min; total glutathione decreased by 52 +/- 5% (p < 0.01) at 60 min. When the ECs were pretreated 30 min before iron loading with 1.25 to 10 microM d-propranolol, glutathione losses were attenuated 15 to 80%, with EC(50) = 3.1 microM. d-Propranolol partially inhibited the DCF intensity increase, but atenolol up to 10 microM was ineffective. At 2 h, caspase 3 activity was elevated 3.2 +/- 0.3-fold (p < 0.01) in the iron-loaded and DHF-treated ECs, and cell survival, determined 24 h later, decreased 47 +/- 6% (p < 0.01). Ten micromoles of d-propranolol suppressed the caspase 3 activation by 63% (p < 0.05) and preserved cell survival back to 88% of control (p < 0.01). In separate experiments, 24-h iron loading resulted in a 3.6 +/- 0.8-fold increase in total EC iron determined by atomic absorption spectroscopy; d-propranolol at 5 microM reduced this increase to 1.5 +/- 0.4-fold (p < 0.01) of controls. Microscopic observation by Perls' staining revealed that the excessive iron accumulated in vesicular endosomal/lysosomal structures, which were substantially diminished by d-propranolol. We previously showed that propranolol could readily concentrate into the lysosomes and raise the intralysosomal pH; it is suggested that the lysosomotropic properties of d-propranolol retarded the EC iron accumulation and thereby conferred the protective effects against iron load-mediated cytotoxicity.

Adrenergic beta-Antagonists↗
PubMed2006

Dose effects of propranolol on cancellous and cortical bone in ovariectomized adult rats.

Animal studies suggest that bone remodeling is under beta-adrenergic control via the sympathetic nervous system. The purpose of this study was to examine the preventive effect of different doses of nonspecific beta-blockers (propranolol) on trabecular and cortical bone envelopes in ovariectomized rats. Six-month-old female Wistar rats were ovariectomized (OVX, n = 60) or sham-operated (n = 15). Then, OVX rats were subcutaneously injected with 0.1 (n = 15), 5 (n = 15), or 20 (n = 15) mg/kg propranolol or vehicle (n = 15) for 10 weeks. Tibial and femoral bone mineral density (BMD) were analyzed longitudinally by dual-energy X-ray absorptiometry. At death, the left tibial metaphysis and L(4) vertebrae were removed, and microcomputed tomography (Skyscan 1072; Skyscan, Aartselaar, Belgium) was performed for trabecular bone structure investigation. Histomorphometry analysis was performed on the right proximal tibia to assess bone cell activities. After 10 weeks, OVX rats had decreased BMD and trabecular parameters and increased bone turnover, as well as cortical porosity compared with the sham group (p < 0.001). Bone architecture alteration was preserved by 0.1 mg/kg propranolol due to higher trabecular number and thickness (+50.35 and +6.81%, respectively, than OVX; p < 0.001) and lower cortical pore number (-52.38% than OVX; p < 0.001). Animals treated by 0.1 mg/kg propranolol had a lower osteoclast surface and a higher osteoblast activity compared with OVX. Animals treated by 20 mg of propranolol did not significantly differ from OVX rats. Animals treated by 5 mg of propranolol have been partially preserved from the ovariectomy. These results showed a dose effect of beta-blockers. The lower the dose of propranolol breeding, the better the preventive effect against ovariectomy.

Animals↗
PubMed1975

Double-blind comparison of tolamolol, propranolol, practolol, and placebo in the treatment of angina pectoris.

Forty-two patients with angina pectoris have completed a randomized, double-blind trial comparing tolamolol 100 mg and 200 mg with propranolol 80 mg, practolol 100 mg, and placebo, all given three times a day. Tolamolol 200 mg thrice daily was found to be equivalent to propranolol 80 mg thrice daily in anti-anginal efficacy. Anginal attack rates and trinitrin consumption were significantly reduced by all active treatments as compared with the placebo but tolamolol and propranolol were the most effective. Tolamolol 200 mg thrice daily was most effective in reducing blood pressure, while propranolol was most effective in reducing the resting heart rate. All treatments except the placebo significantly increased the amount of exercise which could be performed before angina appeared (exercise work), while tolamolol 200 mg thrice daily significantly reduced Robinson's index when compared with all other active agents. The degree of S-T segment depression induced by exercise was significantly lessened by both tolamolol and propranolol but not by practolol or placebo. There was no difference in patient preference between tolamolol and propranolol but tolamolol at both dose levels was preferred to practolol. Both tolamolol and propranolol are potent adrenergic beta-receptor antagonists and equal in anti-anginal efficacy but tolamolol has the advantage of being cardioselective. It is superior to practolol.

Adult↗
PubMed1972

Pharmacodynamics of propranolol in renal failure.

The pharmacodynamics of propranolol were studied in patients with renal functional impairment. (14)C-labelled propranolol was given either intravenously or by mouth and the disappearance rates of propranolol, 4-hydroxypropranolol, and total radioactive metabolites measured. The renal clearance of total radioactive compounds is directly related to renal function. The half-life of total radioactivity is greatly lengthened in the presence of severe renal failure while the half-lives of the pharmacologically active propranolol and 4-hydroxymetabolite are slightly reduced. There is a suggestion that the absorption of propranolol is delayed in renal failure. No known pharmacological action or side effects from the other metabolic products of propranolol have been recognized. There is still too little well-documented evidence concerning the beta-blocking activity of the unidentified major metabolites of propranolol to suggest any alteration in the dosage regimen used in renal failure.

Acute Kidney Injury↗
PubMed1986

Improved myocardial lactate extraction after propranolol in coronary artery disease: effected by peripheral glutamate and free fatty acid metabolism.

Ten patients with chronic effort angina and coronary artery disease (luminal diameter reduction greater than 75%) were stressed by atrial pacing (140 beats/minutes) before and 15 minutes after intravenous propranolol (mean dose 7.4 mg). Myocardial substrate exchange of oxygen, blood lactate, plasma free fatty acids, citrate, glucose, glutamate, and alanine as well as coronary sinus blood flow were measured. Coronary sinus blood flow, oxygen consumption, and systemic haemodynamics did not change after propranolol. Propranolol did not influence arterial lactate concentration, and it reduced the arterial concentration of free fatty acid by 37% and increased that of glutamate by 21%. During pacing myocardial lactate extraction increased in all 10 patients; in two lactate release was converted to lactate uptake. Propranolol reduced free fatty acid uptake and increased glutamate uptake during pacing. For both substances the changes in aortocoronary sinus differences or in uptake or both correlated positively with the changes in their delivery to the heart from extracardial sources (arterial concentrations/loads). In the unstressed state before pacing, aortocoronary sinus lactate differences correlated inversely with free fatty acid differences and positively with those of glutamate. During pacing the relation between lactate and glutamate differences remained positive while the inverse correlation between lactate and free fatty acid differences was lost. Myocardial citrate release was halved during pacing and recovery. Propranolol did not influence alanine or glucose exchanges. An improved myocardial lactate extraction after propranolol administration may be secondary to decreased free fatty acid uptake or increased glutamate uptake or both. In the unstressed state both mechanisms may be of importance. During pacing induced ischaemia, increased glutamate uptake is more likely than reduced free fatty acid uptake to be the mechanism responsible for the improvement in myocardial lactate extraction. The propranolol mediated alterations in myocardial substrate exchanges may reflect the extracardial effects of the drug.

Adult↗
PubMed1979

Relationship between plasma propranolol concentration and relief of essential tremor.

The relationship between plasma propranolol concentration and relief of essential tremor was examined in 11 patients during treatment with oral racemic propranolol in doses of 30 to 640 mg/day. Although propranolol decreased tremor in all 11 patients, the degree of improvement varied widely in individuals (mean 51%, range 25--90%), and was not related directly occurred at plasma propranolol concentrations below 20 ng/ml (0.077 mumol/l) and, in three others, below 40 ng/ml (0.154 mumol/l). It is concluded that the optimum response of essential tremor to propranolol is achieved at relatively low plasma propranolol levels, levels which are obtained by daily propranolol doses of 120--240 mg.

Adult↗
PubMed1982

Controlled study of metoprolol and propranolol during prolonged administration in patients with essential tremor.

The efficacy of propranolol and metoprolol in the treatment of essential tremor was compared in a double blind crossover placebo-controlled study in 16 patients. Each treatment was given for a period of 4 weeks at two different dosage regimens (150 and 300 mg daily for metoprolol, 120 and 240 mg daily for propranolol). Each dosage regimen lasted for 2 weeks. Tremor assessment was carried out by accelerometry, clinical evaluation, patient's self-rating and a battery of performance tests. At the lower dosage, propranolol was found to be superior to placebo on the basis of performance tests and patient's self-assessment. At the higher dosage, propranolol was superior to placebo on all methods of assessment. By contrast, the tremorolytic effect of metoprolol was not significantly different from that of placebo, irrespective of the dosage or of the method of assessment used. Propranolol (120 mg daily) was better than metoprolol (150 mg daily) on the basis of clinical evaluation and patient's self-assessment. Propranolol (240 mg daily) was superior to metoprolol (300 mg daily) on the basis of patient's self-assessment. Both drugs antagonised standing tachycardia to a similar extent. These results indicate that the effectiveness of metoprolol, previously demonstrated in a single-dose study in the same patients, is not fully maintained during prolonged administration. In the absence of specific contraindications, propranolol represents a better choice in the treatment of patients with essential tremor.

Adult↗