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PubMed1977

Studies on the uptake and binding of propranolol by rat tissues.

The tissue distribution of propranolol after i.v. administration (1.5 and 7.5 mg/kg) was studied in rats. Lung, brain and kidney showed extensive propranolol tissue binding. Propranolol uptake by lung seemed to be a saturable process. In contrast to the above tissues, liver propranolol concentrations remained low over the time period of study. An increase in the propranolol T1/2 was noted at the high dose and seemed to result from reduced systemic clearance and an increase in the apparent volume of distribution. Microsomal and mitochondrial fractions from several tissues contained substantial amounts of propranolol after i.v. administration and in vitro incubation with homogenates. Cytosol proteins did not bind significant amounts of propranolol. Equilibrium dialysis studies with rat liver mitochondrial and microsomal fractions revealed both high affinity, low capacity propranolol binding sites and low affinity, high capacity sites. At low concentrations, propranolol interaction with rat liver microsomes produced a type I difference spectrum with high affinity binding of similar magnitude to that observed with equilibrium dialysis. Higher concentrations of propranolol produced a saturable shift in the difference spectra with reduced binding affinity for propranolol. Results from these studies indicate that particulate fractions from several tissues contribute to the extensive tissue binding of propranolol.

Animals↗

PubMed2004

Elution of propranolol as an ion-pair complex by buffer solutions on C18-silica.

Propranolol (pK(a) = 9.4) was eluted on C(18)-bonded Kromasil, equilibrated with buffer solutions of methanol and water (40/60, v/v) containing a constant concentration of a counteranion (12 mM). Nine different counteranions were studied: Cl(-), I(-), NO(3)(-), SO(4)(2-), CH(3)COO(-), HOOCC(2)H(4)COO(-), (-)OOCC(2)H(4)COO(-), HOOCCOHCOOHCOO(-), HOOCCOHCOO(-)COO(-), and (-)OOCCOHCOO(-)COO(-). The co-cation was K(+) or Na(+). Vacancy perturbations were measured on three concentration plateaus of propranolol hydrochloride, at 1.2, 12, and 24 mM, by injecting 100 microL of a pure mixture of methanol and water (40/60, v/v). Indirect detection of the solvent, the counteranion, the co-cation, and the chloride ion was carried out at 325 nm, a wavelength at which only propranolol responds. In a 1.2 mM propranolol hydrochloride solution, there is a 10-fold excess of counteranions and only a positive perturbation peak, due to the excluded co-cation and eluting before the column hold-up time, and a large vacancy peak, associated with propranolol, were recorded. Association between propranolol and the counteranion in excess determines the retention time of this second perturbation. The hydrophobicity of the complexes increases in the order Cl(-) < CH(3)COO(-) approximately HOOCC(2)H(4)COO(-) < NO(3)(-) < I(-) < HOOCCOHCOOHCOO(-) < (-)OOCC(2)H(4)COO(-) < SO(4)(2-) approximately HOOCCOHCOO(-)COO(-) < (-)OOCCOHCOO(-)COO(-). Propranolol retention is larger in the presence of the trivalent citrate anion than in that of the bivalent citrate, succinate, or sulfate anions. It is larger with these bivalent anions than with any monovalent anion. Equal concentration of propranolol hydrochloride and buffer in the mobile phase reveals five system peaks associated with the five components (solvent, counteranion, co-cation, chloride, propranolol molecules). In contrast with monovalent anions, bivalent anions (sulfate, succinate, citrate) or trivalent anions (citrate) cause a reversal of the elution order of the perturbation peaks of chloride anions and buffer molecules. This confirms a competition between chloride and buffer anions to form ion pairs with propranolol. The retention of the perturbation signal of the buffer increases with increasing anion charge because multivalent anions can bind to several molecules of propranolol. The perturbation measurements demonstrate the influence of the valence and hydrophobicity of the buffer on the retention of ionizable compounds. The inverse method allowed the derivation of the isotherm parameters from the overloaded band profiles of propranolol. These values confirm that adsorbate-adsorbate interactions increase with increasing valence of the anions.

Journal Article↗

PubMed1996

Toxic doses of rac-, (-)-(S)- and (+)-(R)-propranolol in rats and rabbits.

The contribution of the individual enantiomers ([+]-[R]- and [-]-[S]-propranolol) to rac-propranolol intoxication was studied in anaesthetized, spontaneously breathing (SB) rats and artificially ventilated (AV) rats and rabbits. In the SB rat, propranolol (30 mg.kg-1.h-1 i.v.) decreased heart rate and mean arterial blood pressure and caused hypoventilation, serious hypoxaemia, respiratory acidosis, and death by respiratory arrest. Survival time (ST) in the (+)-(R)-propranolol group (ST 91 +/- 5 min) was significantly longer than in the rac-propranolol group (ST. 68 +/- 6 min). In AV rats and rabbits toxic doses of rac-, (-)-(S)- and (+)-(R)-propranolol, 30 mg.kg-1.h-1 and 15 mg.kg-1.h-1 i.v., respectively, induced comparable effects on haemodynamic variables as in the SB rat. Artificial ventilation lengthened ST by a factor of three to four in rats. In the AV rat, ST's were not significantly different between the rac-, (-)-(S)- and (+)-(R)-propranolol groups. In the rabbit, as in the SB rat, ST in the (+)-(R)-propranolol group was significantly longer than ST's in the rac- and (-)-(S)-propranolol groups. The acute respiratory acidosis in SB rats and the prolonged ST in AV rats suggest that respiratory failure is the primary and cardiovascular failure the secondary cause of death in propranolol intoxication. The potentiation of the toxic effect of the enantiomers observed after dosing the racemate instead of the pure enantiomers could not be explained by a stereoselective difference in plasma propranolol concentration.

Adrenergic beta-Antagonists↗

PubMed1994

Enantioselective inhibitory effect of nicardipine on the hepatic clearance of propranolol in man.

The influence of a single oral dose of 30 mg nicardipine on the pharmacokinetics of (R)- and (S)-propranolol, given orally as rac-propranolol 80 mg, was studied in 12 healthy volunteers. The plasma concentrations were higher for the (S)-enantiomer than for the (R)-enantiomer. The Cl(o) and the Cl'intr of (S)-propranolol were significantly lower than the Cl(o) and Cl'intr of (R)-propranolol. The unbound fraction of (R)-propranolol was significantly higher than that of (S)-propranolol. Coadministration of nicardipine significantly increased the AUC and Cmax and significantly decreased the Cl(o) and Cl'intr for unbound drug of (R)- and (S)-propranolol. These changes were more important for (R)- than for (S)-propranolol. The protein binding was not altered by nicardipine. The enantioselective effect of nicardipine on the metabolic clearance of propranolol appears to be due to an interaction at the level of the metabolizing enzymes. The effect on blood pressure of rac-propranolol was little affected when nicardipine was coadministered with rac-propranolol, and its bradycardic effect was reduced.

Adult↗

PubMed1979

Effect of furosemide on plasma concentration and beta-blockade by propranolol.

Although propranolol and furosemide are used together for hypertension, the effects of furosemide on plasma levels and beta-blocking action of propranolol are not known. Ten healthy subjects received propranolol 40 mg orally; the mean plasma propranolol levels in 60, 90, 180, and 300 min were 85 +/- 16, 90 +/- 7, 82 +/- 8, and 58 +/- 8 ng/ml. Propranolol was then given together with furosemide (25 mg orally) and the propranolol blood level was measured. Mean propranolol plasma levels were 106 +/- 11 ng/ml at 60 min, 120 +/- 12 ng/ml at 90 min (p less than 0.01), 102 +/- 8 ng/ml at 180 min (p less than 0.05), and 78 +/- 8 ng/ml at 300 min (p less than 0.01). Six additional subjects were given an infusion of 1 microgram/min isoproterenol increased by 0.5 microgram/min every 2 min until the heart rate rose by 25% after oral administration of furosemide 25 mg. This procedure was repeated after propranolol (40 mg orally) and propranolol with furosemide (25 mg orally). The amount of isoproterenol which raised the heart rate by 25% was 2.6 +/- 0.3 micrograms after furosemide alone and 17.7 +/- 2 micrograms after propranolol (p less than 0.01). After propranolol with furosemide the dose of isoproterenol required to elevate heart rate by 25% was 109 +/- 15 micrograms (p less than 0.001).

Adolescent↗

PubMed1989

Influence of nifedipine therapy on indocyanine green and oral propranolol pharmacokinetics.

Nine healthy adults were administered indocyanine green (ICG) 0.5 mg.kg-1 IV alone and after the administration of the following oral drugs: nifedipine 10 mg, propranolol 80 mg, propranolol 80 mg and nifedipine 10 mg, and propranolol 80 mg after nifedipine 10 mg every 8 h for 5 days. Heart rate and mean arterial blood pressure (MAP) were also determined. Nifedipine increased ICG clearance by 14% and decreased t1/2 by 26%. Propranolol decreased ICG clearance by 21% and increased t1/2 42%. Nifedipine and propranolol given together increased ICG clearance 63% and decreased t1/2 by 19%. All changes were statistically significant. Propranolol given after multiple doses of nifedipine did not change ICG kinetic parameters. Propranolol Cmax, tmax, oral clearance, and t1/2 did not change after nifedipine therapy. However, partial propranolol AUC values between 0-0.33, 0-0.5, 0-1.0 and 0-1.5 h were significantly larger after single and multiple doses of nifedipine indicating higher propranolol concentrations during the absorption phase. Heart rate and MAP did not change after nifedipine treatment. Similar declines in heart rate and MAP occurred after propranolol alone and propranolol after single and multiple doses of nifedipine.

Administration, Oral↗

PubMedDate not supplied

H3 Propranolol serum levels following lidocaine administration in rats with CCL4 induced liver damage.

Liver disease alters the pharmacokinetic and pharmacodynamic properties of hepatically eliminated drugs. The main factors influenced are plasma albumin levels, enzyme balance (induction & inhibition) and drug binding to tissue proteins. The influence of lidocaine on serum, heart and liver propranolol levels in Wistar rats after liver injury induced by carbon tetrachloride CCl4 0.4 ml/kg x 2/wkl, was investigated. 40 male Wistar rats were divided into four groups (I, II, III, IV; n=10), Group I animals received only propranolol (labelled + cold substance) 40 mg/kg/12 h p.o., group II propranolol plus lidocaine in a single dose of 4mg/kg s.c., group III was treated with CCl4 for 6 weeks and received propranolol x2 at the same dosage as group I, while group VI was treated with CCl4 and the same drug dosage as group II. The simultaneous administration of H3-propranolol and lidocaine increased propranolol levels in the serum and tissues. The liver in damaged animals showed an increase of propranolol level under lidocaine co-administration, probably due to CCl4 induced liver enzyme activity, resulting in a rapid propranolol metabolism or to competition between both drug protein binding sites. The increased propranolol levels in the heart after lidocaine administration were probably due to attributed to its high affinity for heart tissue. Consequently, as regards the therapeutic approach for patients with liver disease receiving propranolol their propranolol dosage should be reduced when lidocaine is co-administered.

Adrenergic beta-Antagonists↗

PubMed1976

On the nature of protection by propranolol against myocardial necrosis after temporary coronary occlusion in dogs.

Propranolol has been shown to reduce the extent of necrosis that develops after temporary coronary occlusion in dogs. To determine whether this protective action was related to beta adrenergic blockade or to direct effects, necrosis was quantitated in the posterior papillary muscle 2 to 4 days after 40 minute periods of coronary occlusion in anesthetized open chest dogs. Groups of dogs either were untreated or were pretreated with doses of d,l-propranolol, 0.005 to 5 mg/kg body weight, or doses of d-propranolol 2.5 or 5 mg/kg. Necrosis was greatly reduced in dogs treated with 5 mg/kg of d, l-propranolol. This protective effect was significant but quantitatively less with 0.5 and 0.05 mg/kg of d, l-propranolol. A dose of 0.005 mg/kg d, l-propranolol and d-propranolol failed to alter myocardial necrosis significantly. The dose-related reduction of necrosis with d, l-propranolol correlated with a similar dose relation for beta adrenergic blockade and suggested that a protective effect was related to beta blockade. The reduction of necrosis with 0.05 and 0.5 mg/kg of d, l-propranolol (a level at which direct "membrane stabilizing" effects are insignificant) suggested that direct effects were not essential for protection. The negative results with d-propranolol further support our conclusion that propranolol reduces myocardial ischemic injury through beta adrenergic blockade rather than through direct myocardial actions.

Animals↗

PubMed1985

Comparative efficacy and tolerance of esmolol to propranolol for control of supraventricular tachyarrhythmia.

This multicenter, double-blind, randomized, parallel study compared the effectiveness and tolerance of intravenous esmolol with intravenous propranolol in patients with supraventricular tachyarrhythmia (heart rate [HR] greater than 120 beats/min). Efficacy was evaluated in 53 patients receiving esmolol and in 57 patients receiving propranolol. Patients randomized to esmolol received infusions of various doses of esmolol ranging from 50 to 300 micrograms/kg/min (each dose infused for 5 minutes) over a 30-minute titration period with intermittent placebo boluses of propranolol. Those randomized for propranolol received 1 mg/min for the first 3 minutes, and then another 3 mg from minutes 5 to 8 with continuous placebo esmolol infusion during the 30-minute titration period. A therapeutic response, defined by 20% or greater reduction in HR, HR less than 100 beats/min or conversion to normal sinus rhythm, was achieved in 72% of patients on esmolol compared with 69% of patients on propranolol (difference not significant). The therapeutic response was maintained in 67% of patients on esmolol and 58% of patients on propranolol (difference not significant) during a 4-hour maintenance period. Conversion to normal sinus rhythm occurred in 14% of esmolol patients and 16% of propranolol patients during titration and 10% of esmolol and 8% of propranolol patients during maintenance. After discontinuation of study drugs, a more rapid reversal of the reduction in HR was observed in esmolol patients compared with those patients receiving propranolol. Adverse reactions were seen in 29 (45%) patients on esmolol and 11 (18%) patients on propranolol. The principle adverse reaction was hypotension, which was predominantly asymptomatic and found in 23 patients receiving esmolol and 4 receiving propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

PubMed1987

Comparison of ethmozine to propranolol and the combination for ventricular arrhythmias.

A randomized, double-blind, crossover study was performed to evaluate the efficacy and tolerance of ethmozine, propranolol and a combination of ethmozine and propranolol for treatment of ventricular arrhythmias. Twenty-six patients received propranolol, 40 mg, or matching placebo 3 times daily, alone or in combination with ethmozine, 600 to 900 mg/day in 3 equally divided doses, for 1-week periods separated by matching placebo. As determined by 48-hour weekly Holter monitoring, the mean reduction in ventricular premature complex (VPC) frequency was significantly greater with ethmozine (86%) and with ethmozine plus propranolol (90%) than with propranolol (41%) (p less than 0.05). Seventy-five percent of patients had more than a 70% reduction in VPCs with ethmozine plus propranolol, although 70% of patients had an equal degree of suppression with ethmozine alone. Only 2 patients (10%) had the same degree of VPC suppression with propranolol. The results were similar for reductions in pairs of VPCs and VT runs. Two patients discontinued propranolol because of adverse effects, but no patient discontinued ethmozine or combination therapy. Adverse effects were not more frequent with combination therapy. Ventricular function as assessed by echocardiography during drug dosing showed no significant changes from placebo. Ethmozine alone or in combination with propranolol was effective in suppressing VPCs for as long as 1 year in patients who responded. It is concluded that ethmozine alone or in combination with propranolol is well tolerated. Propranolol does not appear to enhance the efficacy of ethmozine.

Anti-Arrhythmia Agents↗

PubMed1990

The antihypertensive drug propranolol enhances LDL catabolism and alters cholesterol metabolism in human cultured fibroblasts.

The effects of 3 beta-blockers with different pharmacological properties (non-selective: propranolol; beta 1-selective: metoprolol; and with intrinsic sympathomimetic activity: pindolol) were comparatively studied on LDL and lipid metabolism in human fibroblasts. At 10(-4) M, propranolol increased low density lipoprotein binding, uptake and degradation by 1.5-, 2.2- and 1.8-fold, respectively, whereas metoprolol and pindolol had no effect. This effect of propranolol is mainly due to an increase in LDL receptor number. Propranolol also enhanced sterol, triacylglycerol, fatty acid and phospholipid synthesis by 2-3-fold from sodium acetate. Cholesterol esterification by oleic acid was significantly and specifically decreased 4-fold by propranolol. Metoprolol and pindolol affect neither sterol synthesis nor cholesterol esterification. Pretreatment of cultured fibroblasts with propranolol induced an increase in hydroxymethyl-glutaryl-coenzyme A reductase activity and a decrease in acyl-coenzyme A: cholesterol-O-acyltransferase (ACAT) activity. Propranolol inhibited the induction of ACAT activity by exogenous cholesterol. Preincubation of a cell-free extract with propranolol also induced inhibition of ACAT activity. Propranolol decreased the cholesteryl ester content of cultured cells. These effects of propranolol on LDL and cholesterol metabolism might be related to the amphiphilic properties of the drug and suggest an effect on the cholesterol intracellular traffic. The decrease in cholesterol esterification and in the cholesteryl ester cellular level induced by propranolol may be involved in its antagonizing effect on experimental atherogenesis.

Cholesterol↗

PubMed1989

Propranolol as xanthine oxidase inhibitor: implications for antioxidant activity.

Propranolol is the beta-blocker most widely used in the management of cardiovascular disorders. It has been proposed that propranolol may act as a "chain-breaking" antioxidant. We have directly examined the ability of propranolol to inhibit superoxide-dependent, iron-promoted cardiac membrane phospholipid peroxidation, with xanthine oxidase (XOD) as a physiologically-recognized, enzymatic superoxide generator. Our results demonstrate that propranolol not only protects cardiac-membrane lipid from peroxidative damage, but also acts as a simple, reversible XOD inhibitor, noncompetitive with xanthine substrate. Propranolol, at effective antiperoxidant and XOD-inhibitory concentrations, cannot scavenge superoxide radical. The antiperoxidative profile of propranolol resembles that of the known XOD inhibitor allopurinol, although allopurinol, a tight-binding substrate-analog competitive with xanthine, inhibits XOD in a manner mechanistically very different from that of propranolol. Furthermore, the antiperoxidative profiles of both propranolol and allopurinol do not resemble those of chain-breaking antioxidants such as alpha-tocopherol. These data, along with the tendency of propranolol to concentrate in myocardial membranes and cytosol, suggest that the observed antioxidant action of propranolol, as a consequence of XOD inhibition, could play a pharmacologic role in propranolol's cardioprotective effects.

Allopurinol↗

PubMed1991

Effects of propranolol on myocardial performance during acute normovolemic hemodilution.

The effects of propranolol and hemodilution on myocardial performance and oxygen delivery were evaluated in 36 anesthetized rats. Oral propranolol treatment consisted of 64 mg/kg/d for 6 weeks prior to the experiments, whereas intravenous (IV) propranolol treatment consisted of 5 micrograms/kg/min for 60 minutes after hemodilution. The hematocrit was reduced to 20% by a hetastarch-for-blood exchange. Animals were divided into six equal groups as follows: (1) no oral drug (water), no hemodilution, no IV drug (saline); (2) oral water, hemodilution, IV saline; (3) oral water, no hemodilution, IV propranolol; (4) oral water, hemodilution, IV propranolol; (5) oral propranolol, no hemodilution, IV saline; and (6) oral propranolol, hemodilution, IV saline. Left ventricular (LV) pressure, maximal dP/dt, ascending aortic blood flow, and response to preload (peak cardiac and stroke volume indices) and afterload (LV-developed pressure) stress were measured. In group 2, hemodilution significantly increased cardiac index, stroke volume index, and dP/dt, and decreased blood pressure, peripheral resistance, and oxygen delivery compared with group 1. Compared with group 2, IV propranolol after hemodilution in group 4 significantly decreased cardiac index, dP/dt, LV-developed pressure, and peak cardiac index, and increased peripheral resistance. Stroke volume index and peak stroke volume index after preload stress remained elevated in group 4, despite the negative inotropic effects of IV propranolol. Oral propranolol in group 6 did not prevent the hemodilution-induced increase in stroke volume index and peak stroke volume index in response to preload stress, although it did decrease cardiac index and dP/dt compared with group 2. Oxygen delivery was reduced in the hemodiluted animals in proportion to the decrease in hemoglobin, regardless of propranolol treatment. It is concluded that reduced myocardial contractility and cardiac performance by nonselective pharmacological beta-adrenoceptor blockade does not interfere with the compensatory increase in stroke volume index after hemodilution.

Administration, Oral↗

PubMed1976

Propranolol in experimental myocardial ischemia: dissociation of effects on contraction and epicardial ST segments.

Recent studies have suggested that propranolol decreases the extent of myocardial injury in acute ischemia. Although other studies have shown that global myocardial performance is depressed, zonal effects of propranolol in this setting are unknown. Therefore, the effect of propranolol (1.0 mg. per kilogram) was investigated in nine dogs with the use of Walton-Brodie strain gauge arches and local epicardial electrograms (10 to 12 sites). The heart rate effects of propranolol were controlled by atrial pacing. After coronary occlusion, heart rate increased slightly without a significant change in blood pressure. Following the infusion of propranolol, heart rate decreased significantly from 165.0 +/- 3.5 to 126.2 +/- 4.7 beats per minute (p less than 0.001) while both the systolic and diastolic blood pressures showed insignificant changes. After coronary occlusion, nonischemic zone tension showed no significant changes; however, propranolol decreased total tension from 105.2 +/- 2.5 per cent to 66.8 +/- 4.7 (p less than 0.001). Similarly, propranolol further decreased total tension in the border zone from 84.4 +/- 6.7 per cent (p less than .02) to 50.6 +/- 5.1 (p less than 0.01). Ischemic zone tension also fell further (p less than 0.025) after propranolol. Restoration of prepropranolol heart rate had no significant effect on tension development. Following coronary occlusion, sigmaST increased from 5.7 +/- 2.2 to 72.9 +/- 20.1 mv. (p less than 0.001). Coincident with the decrease in heart rate and tension development induced by propranolol, sigmaST decreased to 60.8 +/- 18.8 mv. (p less than 0.05). When the heart rate was restored to prepropranolol level, sigmaST again rose to 73.2 +/- 16.9 mv. (p less than .005). Thus, propranolol does effect an improvement in ischemic injury which is related, at least in part, to the induced decrease in heart rate. A concomitant substantial decrease in local tension development also occurs, however. The latter observations may limit the potential usefulness of propranolol in this setting.

Animals↗

PubMed1985

Rapid and simultaneous extraction of propranolol, its neutral and basic metabolites from plasma and assay by high-performance liquid chromatography.

A high-performance liquid chromatographic method is described for the determination of propranolol, its neutral and basic metabolites from a single plasma sample. These analytes were extracted simply and efficiently by a solid-phase extraction column based on C18 modified silica (C18 Bond-Elut). Propranolol, the 4-hydroxy and N-desisopropyl metabolites were separated on a mu Bondapak C18 column with a mobile phase of acetonitrile--0.1% phosphoric acid. Propranolol glycol was selectively eluted from the C18 Bond-Elut column with acetonitrile and chromatographed separately with a mobile phase of acetonitrile--water. The recoveries of propranolol and all metabolites were greater than 78% with an intra-assay coefficient of variation between 4.9 and 7.3% at a concentration of 5-50 ng/ml. The minimum detectable levels in 1 ml of plasma were 1.0 ng/ml propranolol, 6.0 ng/ml 4-hydroxypropranolol, 1.0 ng/ml N-desisopropylpropranolol and 2.5 ng/ml propranolol glycol. Enzyme hydrolysis, Bond-Elut extraction and high-performance liquid chromatography revealed that propranolol, the neutral and basic metabolites were extensively conjugated in dog plasma (propranolol 67%, 4-hydroxypropranolol 98%, N-desisopropylpropranolol 55% and propranolol glycol 80%). With the use of pure enzymes and a selective inhibitor the nature of this conjugation appeared to involve both glucuronidation and sulfation. The conjugation of propranolol involved mainly glucuronidation (58-62%) compared to sulfation (7-12%), whilst that of 4-hydroxypropranolol mainly involved sulfation (55-65%) compared to glucuronidation (32-38%). The values for N-desisopropylpropranolol and propranolol glycol were 26-31% and 12% sulfation, 16-29% and 68-85% glucuronidation, respectively.

Chromatography, High Pressure Liquid↗

PubMed1981

No stereoselective first-pass hepatic extraction of propranolol.

The plasma level: time profile for l-propranolol and total propranolol concentrations were examined in normotensive subjects after intravenous and oral dl-propranolol. l-Propranolol concentrations in plasma accounted for about 60% of total propranolol. This was attributed to lower volume of distribution for the isomer. Mean plasma clearance of 1-propranolol was similarly affected while apparent plasma half-life for the l-isomer and total propranolol were of the same order. Oral bioavailability of 1- and total propranolol averaged 40.7 +/- 8.5% and 42.4 +/- 12.9%. Food and hydralazine increased oral bioavailability of total and l-propranolol by similar magnitudes. We conclude that difference in the kinetics of l- and total propranolol concentrations in plasma are small and probably of no clinical significance. Presystemic clearance of propranolol in man does not appear to be stereospecific.

Administration, Oral↗

PubMed2002

Efficacy and tolerability in migraine prophylaxis of flunarizine in reduced doses: a comparison with propranolol 160 mg daily.

This was a phase-IV double-blind equivalence trial designed to assess the efficacy and tolerability of two doses of flunarizine (10 mg o.d.=FLU 10 mg and 5 mg o.d.=FLU 5 mg) in the prophylaxis of migraine, in comparison with slow-release propranolol (160 mg o.d.). A total of 808 subjects were treated in a treatment period of 16 weeks. 142 subjects discontinued the trial prematurely, mainly because of adverse events (n=58). The mean attack frequency in the double-blind period was 2.0 for the FLU 5 mg group, 1.9 for the FLU 10 mg group, and 1.9 for the propranolol group. The mean attack frequency in the last 28 days of the double-blind period was 1.8 for FLU 5 mg, 1.6 for FLU 10 mg, and 1.7 for propranolol. Both flunarizine groups were at least as effective as propranolol (P<0.001 in one-sided test). The percentage of responders (defined as subjects for whom attack frequency decreased by at least 50% compared to run-in) in the last 28 days of the double-blind period was 46% (118/259) for FLU 5 mg, 53% (141/264) for FLU 10 mg, and 48% (125/258) for propranolol. Statistical analysis showed that FLU 10 mg is at least as effective as propranolol (P<0.001) and showed a trend for noninferiority of FLU5 and propranolol (P=0.053). No statistically significant differences between the treatment groups were found for any of the secondary parameters. Overall, 190 subjects reported one or more adverse events during the run-in phase: 54 (20.5%) in the FLU 5 mg group, 76 (27.7%) in the FLU 10 mg group and 60 (22.3%) in the propranolol group. The results of this equivalence trial show that 10 mg flunarizine daily with a drug-free weekend is at least as effective as 160 mg propranolol in the prophylaxis of migraine for all evaluated parameters (one-sided equivalence tests) after 16 weeks of treatment. In addition, 5 mg flunarizine proves to be at least as effective as 160 mg propranolol when looking at the mean attack frequency for both the whole double-blind period and the last 28 days of treatment. However, in the analysis of responders, 160 mg propranolol seems to be slightly better than 5 mg flunarizine. In addition, no significant differences between the three treatments were found with regard to safety: all three treatments were generally well-tolerated and safe.

Adolescent↗

PubMed1987

Metabolic effects of verapamil and propranolol during submaximal endurance exercise in patients with essential hypertension.

In contrast to beta-adrenoceptor blocking agents, calcium channel blockers do not appear to affect exercise tolerance in hypertensive subjects. A possible explanation is a difference in the metabolic effects of both types of drugs. Therefore, the effects of 4-week treatment periods with verapamil and propranolol on metabolic parameters during an endurance bicycle ergometer test were studied in eight patients with mild to moderate essential hypertension. Patients exercised at a work load which increased the heart rate to 150 bts/min during placebo. A single-blind, placebo-controlled, randomized cross-over design was used. The dose of propranolol and verapamil was adjusted to lower standing diastolic blood pressure less than 90 mmHg. Average daily doses were 155 +/- 21 mg propranolol and 390 +/- 44 mg verapamil. Exercise heart rate was reduced during propranolol and verapamil (P less than 0.01), but the reduction was more pronounced during propranolol than during verapamil (P less than 0.05). Minute ventilation and oxygen consumption were unchanged during propranolol and verapamil. The respiratory exchange ratio tended to increase during propranolol. Plasma glucose and lactate concentrations were unchanged during propranolol and verapamil. In contrast, plasma glycerol and nonesterified fatty acids were reduced during propranolol (P less than 0.05), but unchanged during verapamil. Plasma potassium levels were increased during propranolol (P less than 0.05). Despite the important direct and indirect role of calcium ions in the regulation of many metabolic processes, no effect of verapamil on metabolic parameters during submaximal exercise was found. In contrast, propranolol had an effect on fat and potassium metabolism during exercise.

Adult↗