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PubMedDate not supplied

Glucuronidation of propranolol and 4'-hydroxypropranolol. Substrate specificity and stereoselectivity of rat liver microsomal glucuronyltransferases.

Liquid-chromatographic procedures were developed to assay the formation of diastereomeric glucuronides of propranolol (PG) and 4'-hydroxypropranolol (HPG) by rat liver microsomes, with identifications performed by GC/MS techniques. Propranolol was conjugated at a rate 10% of that determined for 4'-hydroxypropranolol. Glucuronyltransferase activity increased slightly (10-17%) in the presence of MgCl2. Inclusion of 0.04% Triton X-100 produced a 55% inhibition of PG formation, but increased HPG formation greater than 2-fold. Pretreatment of animals with phenobarbital resulted in a 4-fold increase in PG formation, but did not affect HPG formation unless MgCl2 was also present. Under these conditions, a 50-60% increase in HPG formation occurred. Pretreatment with 3-methylcholanthrene did not affect the formation of either glucuronide. (R)-(+)-Propranolol was glucuronidated 2-fold faster than the (S)-(-) enantiomer at substrate concentrations below 0.1 mM, and 1.3-fold faster at substrate concentrations above 2.0 mM. The estimated Vmax, 0.67 nmol/mg/min, was identical for both enantiomers. The dissociation constants were significantly different, however, being 0.57 mM for (R)-(+)-propranolol and 0.87 mM for (S)-(-)-propranolol. No stereoselectivity was observed in the formation of HPG when 4'-hydroxypropranolol was used as substrate, or when propranolol was incubated in the presence of an NADPH-generating system. Propranolol and 4'-hydroxypropranolol were used as substrate, or when propranolol was incubated in the presence of an NADPH-generating system. Propranolol and 4-hydroxypropranolol are apparently glucuronidated by different forms of rat liver glucuronyltransferase. Furthermore, propranolol glucuronidation occurs stereoselectively in vitro because of the different enzyme affinities for the enantiomers of the drug.

Animals↗
PubMedDate not supplied

N-dealkylation of propranolol in rat, dog, and man. Chemical and stereochemical aspects.

Chemical and stereochemical aspects of the metabolic N-dealkylation pathway of propranolol were examined in rat, dog, and man. Metabolites arising from pseudoracemates of propranolol were analyzed by GC-MS. In the presence of the rat liver 9000g supernatant fraction, desisopropylpropranolol arose primarily from R-propranolol while subsequent metabolites of this pathway were formed preferentially from S-propranolol. Small amounts of these metabolites (less than 3% of a 20 mg/kg ip dose) were also found as urinary metabolites in the rat. The formation of the two acidic metabolites, naphthoxylactic acid (NLA) and naphthoxyacetic acid, was stereoselective from S- and from R-propranolol, respectively. The stereochemical results from NLA formation in man in vivo were similar to those in rats, being stereoselective for S-propranolol. However, in dog administered pseudoracemic propranolol by iv infusion, more R-than S-propranolol was converted to NLA. In all experiments, in vitro (rat liver 9000g supernatant fraction) and in vivo (rat, dog, and man), the naphthoxyacetic acid formed arose preferentially from R-propranolol, when compared to the stereochemical origin of NLA. In vitro metabolism of the enantiomers of NLA also yielded significantly more naphthoxyacetic acid from the S-enantiomer of NLA (stereochemically related to R-propranolol). These results are consistent with a stereoselective conversion of S-NLA to naphthoxyacetic acid, possibly via enzymes similar to L-lactate dehydrogenase.

Adult↗
PubMed1981

The inhibitory effect of propranolol pretreatment on its own metabolism in the rat.

Repetitive oral administration of propranolol to rats (100 mg/kg/day for 5 days) resulted in a marked inhibition of hepatic microsomal metabolism of propranolol when incubated at low initial substrate concentrations (less than 2 microM). Associated with the inhibition of propranolol metabolism was a significant reduction in metabolites derived from naphthalene ring oxidation and an increased formation of N-desisopropylpropranolol. In vivo studies after propranolol pretreatment resulted in: an increased hepatic concentration and an increased systemic availability of propranolol; a decreased hepatic and plasma concentration of polar metabolites; and an increased plasma concentration of metabolites derived from propranolol N-dealkylation. Propranolol was converted both in vitro and in vivo by a hepatic microsomal mixed-function oxidase to a reactive metabolite capable of covalently binding with microsomal macromolecules. We propose that selective covalent binding of the reactive intermediate to the molecular form of cytochrome P-450 that ring hydroxylates propranolol would account for the marked inhibition of propranolol metabolism in vitro and for the increased systemic availability of propranolol in vivo after pretreatment.

Animals↗
PubMed1983

Stereoselective increase in propranolol bioavailability during chronic dosing in the dog.

The disposition of (+)- and (-)-propranolol was determined after chronic as compared to single oral doses of racemic drug. Single oral doses (80 mg) of a stable isotope-labeled pseudoracemate were given to six dogs before and after chronic pretreatment with unlabeled propranolol. The bioavailability of (-)-propranolol (5.7 +/- 1.6%; mean +/- S.E.) was considerably lower (P less than .01) than that of (+)-propranolol (16.1 +/- 5.9%) after single doses. Chronic pretreatment led to a 167% increase in the bioavailability of (-)-propranolol to 15.2 +/- 3.7% (P less than .01), with only a 47% increase in (+)-propranolol to 23.7 +/- 4.5% (N.S.). Chronic pretreatment had no effect on the kinetics of i.v. doses of tritium-labeled racemic drug administered simultaneously or on blood binding. This stereoselective increase in the bioavailability of (-)-propranolol was associated with an unexpected 62% increase in the glucuronidation of this enantiomer (P less than .01) with no effect on the glucuronidation of (+)-propranolol. There was, however, a change in the stereochemical composition of 4'-hydroxypropranolol from single doses, (-)/(+)-enantiomer ratio 1.37 +/- 0.14, to chronic doses, 1.23 +/- 0.13 (P less than 0.05), suggesting stereoselective inhibition of ring-oxidation of (-)-propranolol. This study demonstrates preferential presystemic hepatic removal of (-)-propranolol in the dog by a process, probably ring-oxidation, that becomes partially inhibited after chronic doses, leading to a stereoselective increase in the bioavailability of this enantiomer.

Animals↗
PubMed1982

Oxidation of (R)- and (S)-propranolol in human and dog liver microsomes. Species differences in stereoselectivity.

Propranolol is an adrenergic beta receptor antagonist whose kinetics is complicated by dose-dependency, formation of active metabolites and stereoselective availability. To get some insight of the possible metabolic factors behind this, we have incubated the two optical isomers (R)- and (S)-propranolol with human and dog liver microsomes. Propranolol and its oxidized metabolites 4-hydroxypropranolol (4-OH-P) and N-desisopropylpropranolol (nor-P) were analyzed using high-performance liquid chromatography and fluorometric detection. The oxidation rates varied markedly between human livers. Most of metabolized propranolol was recovered as 4-OH-P and nor-P and more propranolol was oxidized than glucuronidated. Formation rates of 4-OH-P and nor-P were approximately half-maximal at propranolol concentrations than can occur in the liver in vivo. The ratio between formation of these metabolites varied markedly between livers. Human livers formed 4-OH-P and nor-P most rapidly from (R)-propranolol, whereas dog livers formed 4-OH-P most rapidly from (S)-propranolol. We suggest that the interindividual differences in the capacity of the livers to metabolize propranolol largely should contribute to the kinetic variations observed between patients in vivo and the gradual saturation of 4-hydroxylation and N-desisopropylation of propranolol are likely to contribute to the dose-dependent kinetics.

Adult↗
PubMed1995

Fetal hepatic propranolol metabolism. Studies in the isolated perfused fetal sheep liver.

We have used an isolated perfused fetal sheep liver preparation to study the fetal hepatic metabolism of propranolol in vitro in the intact organ. Eight livers were perfused in situ via the umbilical vein in an oxygenated recirculating system at 300 ml/min. Radiolabeled 15-microns microspheres were used to quantify the hepatic ductus venosus shunt. Propranolol (4 mg) was dosed into the reservoir as a single bolus and perfusate and bile sampled over 150 min. Propranolol, 4-hydroxy propranolol (4OHP), 5-hydroxy propranolol (5OHP), desisopropylpropranolol (DIP), naphthoxylactic acid (NLA), and alpha-naphthoxyacetic acid (NAA) were assayed by HPLC, before and after deconjugation by enzyme hydrolysis. Mean age was 125 +/- 10 days, and mean liver weight was 66.1 +/- 18.8 g. Oxygen consumption (1.10 +/- 1.03 mumol/g/min), bile flow (0.51 +/- 0.18 microliters/g/min), and perfusion pressure (8.7 +/- 3.3 mm Hg) were stable. Ductus venosus shunt was 41.6 +/- 17.4% of umbilical vein flow. Propranolol clearance was 26.2 +/- 13.4 ml/min, and shunt-corrected extraction of propranolol was 0.26 +/- 0.13. The relative amounts of metabolites in perfusate after 150 min were: 4OHP (25.1%), 5OHP (5.08%) (ring-oxidation products), DIP (6.57%), and NLA (4.33%) (side-chain oxidation products). No alpha NAA (a product of N-dealkylation of NLA) was detected. Except for NLA, metabolites were present predominantly as conjugates. Biliary excretion of unchanged drug and metabolites accounted for a further 1.33% of the propranolol dose. These data indicate that, although the hepatic clearance and extraction of propranolol are low, the fetal sheep liver can metabolize propranolol by both ring- and side-chain oxidation reactions and can conjugate these metabolites.

Animals↗
PubMed1977

Beneficial effect of propranolol in a histologically appropriate model of postischemic acute renal failure.

Acute renal failure caused in the rabbit by clamping one renal pedicle for 1 hour and removing the opposite kidney produced a histologic picture very similar to that observed in "hypotensive" acute renal failure in man. Intravenous infusion of propranolol, a drug which prevents renin release, at 1 mg/kg for 70 minutes beginning at time of pedicle clamping resulted in significantly lower serum creatinine in this model (2.8 +/- 0.2 mg% at 48 hours with propranolol versus 5.2 +/- 0.8 mg% without). Renin stimulation by dehydration or feeding a low-salt diet enhanced the difference between treated and untreated groups (2.6 +/- 0.4 mg% with propranolol versus 6.2 +/- 1.8 mg% without, after dehydration; 3.5 +/- 1.0 mg% with propranolol versus 7.6 +/- 1.4 mg% without, after low-salt diet).Suppression of renin production by saline feeding eliminated propranolol's beneficial effect (5.6 +/- 0.9 mg% with propranolol versus 4.0 +/- 0.6 mg% without). In rabbits with a normal food and water intake, renal denervation using phenol also eliminated propranolol's effect (creatinine 8.6 +/- 1.4 mg% with propranolol versus 8.6 +/- 1.8 mg% without). In rabbits with intact kidneys, flow probe recording of renal blood flow showed a significantly higher blood flow immediately after unclamping in the propranolol-treated animals, and renal angiograms showed less vasoconstriction in this group after unclamping. In this model of acute renal failure, renal vasoconstriction plays an important role following the initial ischemic insult. Propranolol lessens the severity of this vasoconstriction and the resulting acute renal failure. Its probable action is interference with neurogenically stimulated renin release.

Acute Kidney Injury↗
PubMed1996

Clearance by the liver in cirrhosis. III. Propranolol uptake by the isolated perfused human liver.

In cirrhosis, intrahepatic shunts and capillarization of sinusoids can result in impaired extraction of substrates by the liver irrespective of the metabolic capacity of the liver (intact hepatocyte theory). To evaluate the role of anomalies of uptake in impaired drug disposition, we studied the steady-state hepatic clearance and single-pass hepatic uptake of propranolol in isolated perfused livers obtained from patients with cirrhosis at the time of transplantation and from organ donors with normal liver architecture. The kinetics of propranolol transport in the liver were characterized by means of the multiple-indicator dilution technique, and the outflow pattern of propranolol in the hepatic veins was resolved into throughput material, which had swept past the hepatocytes along with albumin, and returning material, which had entered the cells but returned in the outflow after escaping cellular sequestration and metabolism. The steady-state clearance of propranolol was decreased in cirrhotics compared with organ donors, and the outflow profile differed between the two groups. In cirrhotic livers, half of the propranolol in the outflow consisted of throughput material and the other half of returning material; in organ donors, all of the propranolol in the outflow was returning material. In the presence of albumin and alpha 1-acid glycoprotein in the perfusate, about 80-85% of propranolol was protein bound; removal of albumin and alpha 1-acid glycoprotein from the perfusate it cirrhotic livers resulted in an increase in the free fraction of propranolol, an increase in steady-state extraction, and a decrease in the throughput component of propranolol in the outflow. We conclude that impaired uptake of protein-bound propranolol, as a result of capillarization and intrahepatic shunts, contributes to its impaired elimination in cirrhosis.

Biological Transport↗
PubMed1984

The influence of bile salts on the absorption in vitro and in vivo of propranolol.

The lipophilicity of propranolol is increased by some bile salts which form ion-pairs. In the presence of taurodeoxycholate, the logarithm of the apparent partition coefficient (log P) of propranolol is increased. Moreover, the apparent diffusion constants in vitro of propranolol as ion-pairs at pH 3.0-6.0 are about 5-6 times higher than those of propranolol alone. The area under the curve values of plasma concentration-time profiles of propranolol, following its oral administration to rabbits together with taurodeoxycholate, are about 1.4 times higher than those after administration of propranolol alone. Moreover, after the administration of propranolol with taurodeoxycholate the plasma concentration rises more rapidly, with a point of inflection between 0.5 and 1.5 h, than after administration of propranolol alone. Taurodeoxycholate does not modify the first-pass effect of propranolol in rabbits following intravenous and intraportal administration. The absorption of an oral dose of propranolol in the presence of taurodeoxycholate increases from 70% to 100%, due to the higher lipophilicity of the ion-pair. The plasma concentration-time curves suggest the hypothesis that greater absorption of the ion-pair occurs mainly in the upper region of the gastrointestinal tract.

Journal Article↗
PubMed1997

Sotalol Is More Powerful Than Propranolol in Suppressing Complex Ventricular Arrhythmias.

BACKGROUND: Sotalol has combined type II and type III antiarrhythmic properties. Although the beta-blocking action of sotalol is thought to contribute to its antiarrhythmic actions, few data are available from direct comparative clinical trials with pure beta-blocking drugs. METHODS AND RESULTS: In this double-blind, randomized, multicenter, placebo-controlled, parallel study, we have compared the antiarrhythmic efficacy and safety of treatment with sotalol vs propranolol in 181 patients with organic heart disease and frequent (>30 ventricular premature complexes [VPCs]/h) repetitive ventricular premature complexes. Eighty-seven were randomized to receive sotalol and 94 received propranolol. The demographic and clinical characteristics of the two groups were identical, and the majority of patients had coronary artery disease or hypertensive heart disease. Most patients had a long-standing history (>5 years) of ventricular arrhythmias and, in a significant proportion, antiarrhythmic therapy with other drugs had failed in the past. After withdrawal of all antiarrhythmic drugs and 1 week of placebo, qualified patients were randomized to sotalol (320 mg/day) or propranolol (120 mg/day). patients not achieving adequate response were given higher doses of sotalol (640 mg/day) or propranolol (240 mg/day)At baseline, both groups had comparable frequency of total VPCs/hour (274/h and 255/h for sotalol and propranolol groups, respectively) which was reduced to 71 VPCs/h and 109/VPCs/h, respectively, at the end of phase 1. At final evaluation there was a significantly greater response to sotalol as demonstrated by 80% reduction in VPCs/hour with sotalol compared with only 50% reduction noted in the propranolol group. Adequate therapeutic response was also achieved in a significantly greater percentage of patients on sotalol compared with propranolol (56% vs 29%, P =.02). Sotalol was also superior to propranolol in suppressing the VT events/day during phase 1 (89% vs 78% reduction in VT events/day, P <.05). Sotalol was more effective than propranolol in all subgroups and in patients with heart rate <75 beats per minute. CONCLUSIONS: Sotalol is more powerful than propranolol in suppressing ventricular arrhythmias documented on Holter recordings. The superiority of sotalol appears to be related to its combined class II and class III antiarrhythmic actions.

Journal Article↗
PubMed1993

Pharmacokinetics of D-propranolol following oral, intra-arterial and intraportal administration: contrasting effects of oral glucose pretreatment.

Several research groups have reported that in man the oral administration of propranolol with food leads to a marked increase (about 50 per cent) in the area under the plasma concentration-time curve (AUCpo) of this well absorbed and highly metabolized drug. An acute change in hepatic metabolic enzyme activity has been postulated as one of the mechanisms which could be responsible for this observed 'food effect'. The administration of simple carbohydrates such as glucose and fructose has been documented to influence hepatic drug metabolism. Therefore, in the present study, the effect of oral glucose (4 g kg-1 as a 50 per cent aqueous solution) on the disposition kinetics of d-propranolol was examined in male Sprague-Dawley rats (8 to 9 per group). Oral glucose treatment caused a statistically significant decrease (50.4 +/- 12.3 vs 36.6 +/- 15.2 min micrograms ml-1; p < 0.05) in the AUCpo of propranolol when this drug was given by oral intubation (10 mg kg-1). This glucose treatment also caused the apparent mean residence time of propranolol after an oral dose to increase from 0.70 +/- 0.08 h to 1.79 +/- 0.29 h (p < 0.05), but did not change its rate of elimination (suggesting collectively a decreased apparent intrinsic clearance and prolonged drug absorption). In a second study, the same oral glucose treatment was demonstrated to have little impact on the steady state concentrations of propranolol when this drug was infused intraarterially at a constant rate. This confirms that the systemic clearance of propranolol is influenced minimally by the glucose treatment. In a third study, propranolol was infused at a constant rate into the portal vein (pyloric vein infusion) bypassing the processes of intestinal metabolism and absorption (i.e. to remove these sources of variability associated with oral administration). Under these conditions, no significant changes in AUC or apparent mean residence time were observed for the two propranolol doses studied (10 mg kg-1 and 5 mg kg-1). We conclude that the oral glucose and oral propranolol interaction appears to be due to an alteration in the input process before drug enters the liver. Furthermore, this experimental series suggests that studies combining accurate assessments of systemic clearance (constant rate intra-arterial infusion studies), intrinsic hepatic clearance (pyloric vein infusion studies), and oral administration supplemented with necessary protein binding studies may be used together to characterize the mechanism responsible for drug-nutrient and drug-drug interactions.

Administration, Oral↗
PubMed2004

Direct determination of S-(-)- and R-(+)-propranolol glucuronide in rat hepatic microsomes by RP-HPLC.

Propranolol, available commercially as a racemic mixture, is a non-selective beta-adrenergic blocking agent used in the treatment of hypertension, angina pectoris and cardiac arrhythmias. We have developed and validated an RP-HPLC assay method for direct determination of R-(+)- and S-(-)-propranolol glucuronide in rat hepatic microsomes to investigate the enantioselectivity of propranolol glucuronidation metabolism. A baseline separation of propranolol glucuronide enantiomers was achieved on a 5 microm reversed-phase ODS column, with a mixture of phosphate buffer (pH 3.5, 0.067 mol/L) and methanol (55:45, v/v) as mobile phase. Ultraviolet detection was set at 220 nm, and p-nitrobenzoic acid was used as internal standard. The standard curve of assay for R-(+)- and S-(-)-propranolol glucuronide in spiked microsomal incubate showed good linearity throughout the concentration range from 0.50 to 20.0 micromol/L. The analytical method affords average recovery of 99.8 and 100.1% for R-(+)- and S-(-)-propranolol glucuronide, respectively. The method provides a high sensitivity and good precision for R-(+)- and S-(-)-propranolol glucuronide (RSD < 10%). The LOD was 0.15 micromol/L and the LOQ was 0.5 micromol/L (RSD < 8%, n = 5) for both R-(+)- and S-(-)-propranolol glucuronide. The method is simple, precise and accurate, and is suitable for quantifying the propranolol glucuronides enantiomers in rat hepatic microsomes.

Adrenergic beta-Antagonists↗
PubMed1993

Propranolol has direct antithyroid activity: inhibition of iodide transport in cultured thyroid follicles.

The effect of propranolol on the process of thyroid hormone formation was studied in a physiological culture system. Porcine thyroid follicles were preincubated with propranolol for 24 h. Iodide transport, iodine organification, and de novo thyroid hormone formation were measured by incubating these follicles with the mixture of carrier-free 0.1 microCi Na125I and 50 nM NaI for 2 to 6 h at 37 degrees C. A concentration of propranolol greater than 100 microM inhibited iodide transport in a dose-dependent manner; this inhibition was non-competitive with iodide and independent of thyrotropin (TSH). Reduced iodine organification and thyroid hormone formation was seen with 150 microM propranolol or greater. The inhibitory action of propranolol was not caused by beta-blocking activity, since D-propranolol (devoid of beta-blocking activity) inhibited iodide transport, and other beta-blockers (metoprolol, atenolol, and labetalol) did not inhibit iodide transport. The inhibition of iodide transport was most likely caused by membrane stabilizing activity since quinidine, which possesses the same membrane stabilizing activity as propranolol, also inhibited iodide transport. TSH-mediated cAMP generation and Na+K+ ATPase activity, membrane functions for iodide transport, were unaffected by propranolol. Our study has shown, for the first time, that propranolol has a direct antithyroid action, namely inhibition of iodide transport in the intact thyroid follicle.

Adrenergic beta-Antagonists↗
PubMed1989

Stereochemistry of tissue distribution of racemic propranolol in the dog.

Only limited information is available on the stereochemistry of the in vivo distribution of beta-receptor-blocking drugs. In this study we determined the levels of the propranolol enantiomers in plasma, cerebrospinal fluid (CSF) and central nervous system (CNS), and peripheral tissues in the dog following an intravenous dose of a deuterium-labeled pseudoracemate. The appearance of the propranolol enantiomers in the CSF was rapid and nonstereoselective, with maximum concentrations reached at 15 min after dosing. The levels of the enantiomers in both CSF and plasma then declined in a parallel biphasic fashion, with a terminal t1/2 of about 125 min. Except for an early high CSF/plasma concentration ratio of 0.35, the CSF propranolol levels corresponded to the unbound concentration in plasma, CSF/plasma 0.20. All areas of the brain showed a similar uptake of propranolol, with a tissue concentration exceeding that in plasma about 10-fold during the terminal phase of elimination. The uptake of propranolol by peripheral tissues varied widely, ranging from a 50-fold accumulation by the lungs compared to plasma to no accumulation by adipose tissue. However, as for the CSF, there was no evidence of stereoselective uptake of propranolol by any CNS or peripheral tissue except for the liver. A significantly higher level of (+)-vs. (-)-propranolol in liver tissue presumably was a reflection of stereoselective hepatic metabolism of (-)-propranolol by this tissue. The slight stereoselectivity in plasma binding of propranolol known to exist in the dog had no significant influence on tissue or CSF distribution.

Animals↗
PubMed1977

Pathophysiologic and pharmacokinetic determinants of the antihypertensive response to propranolol.

The tendency for patients with essential hypertension to differ markedly in antihypertensive response to propranolol could arise from pathophysiologic or pharmacokinetic differences between them. This possibility was investigated in 23 men with mild to moderately severe essential hypertension. At each of three propranolol doses, 40 mg, 80 mg, and 320 mg daily, approximately a 20-fold range in steady-state plasma propranolol concentrations was observed. Clinical response however was unrelated to plasma propranolol: oral dose ratio, since patients with higher plasma levels were less sensitive to the existing plasma drug concentration. When falls in blood pressure and plasma propranolol concentration were compared overall, a biphasic dose-response relationship was noted, with a first component at plasma propranolol concentrations of 3 to 30 ng/ml and a second at concentrations above 30 ng/ml. Only patients with increased sympathetic nervous system activity and high plasma renin activity (PRA) had substantial falls in pressure at propranolol levels of 3 to 30 ng/ml. Cardiac beta adrenergic receptor blockade, not suppression of PRA, seemed to be the antihypertensive mechanism. This relation of pretreatment sympathetic nervous activity and PRA to antihypertensive response existed only at lower plasma propranolol concentrations. With a propranolol dose of 320 mg daily, both plasma norepinephrine concentration and PRA were unrelated to the clinical response.

Adolescent↗
PubMed1979

Effects of atenolol and propranolol when added to long-term antihypertensive diuretic therapy.

The antihypertensive effects of atenolol and propranolol were compared in a double-blind crossover study of 19 patients with essential hypertension (World Health Organization, I and II) who were receiving long-term diuretic treatment (chlorthalidone, 50 mg daily) during the study. After a 3-wk placebo period, a beta-adrenergic antagonist was administered once daily (atenolol, 50 mg daily, or propranolol, 80 mg daily) for a week. If the MAP was more than 108 mm Hg at the end of the week, dosage of the beta-blocker was doubled the following week; when necessary, doubling was repeated to a maximum dose of 640 mg propranolol and 400 mg atenolol daily. Fifty milligrams atenolol had a greater effect than 80 mg propranolol and was as effective as 160 mg propranolol. The dose-response curve flattened off after 160 mg propranolol and 50 mg atenolol daily. The two highest doses of atenolol lowered MAP more than the highest doses of propranolo. Heart rate slowing was the same for both drugs and did not correlate with the fall in blood pressure. PRA was suppressed by all doses of propranolol, whereas atenolol suppressed PRA only at the 2 highest doses, (200 and 400 mg daily). With the lower propranolol doses, the percent MAP change correlated weakly with the percent PRA change (80 mg--r = 0.41, p less than 0.1; 160 mg--r = 0.64, p less than 0.05). Side effects were minimal, and were noted only with 640 mg propranolol; with this exception, the percentage of patients with no complaints rose when placebo was replaced by beta-blockers.

Administration, Oral↗
PubMedDate not supplied

Effect of propranolol on hepatic and systemic hemodynamics in dogs with chronic bile duct ligation.

Propranolol has been reported to reduce portal and wedged hepatic vein pressures in man and may be useful for the prevention of variceal bleeding. However, its mechanism of action remains unclear. We have examined the effect of propranolol on the systemic and hepatic circulations in dogs with chronic bile duct ligation and secondary biliary cirrhosis. Under anesthesia, eight dogs received four increasing doses of propranolol as an i.v. bolus followed by continuous infusion. Systemic and hepatic hemodynamic parameters were measured in basal conditions and after a 30 min infusion for each dose. Portal vein and hepatic artery blood flows were measured with electromagnetic flow meters. All dogs had portal hypertension (portal venous pressure 15.3 +/- 0.8 mm Hg), a hyperdynamic circulation and severe liver disease resulting in a marked decrease of propranolol systemic clearance (8.75 ml per min per kg) and extraction (40%). The first dose of propranolol induced a decrease in heart rate (-27%) and in cardiac index (-21%), and an increase in systemic vascular resistance (+20%). With increasing doses, the systemic vascular resistance decreased with an increase in the cardiac index. Propranolol was not associated with significant modifications of hepatic hemodynamics: portal, wedged and free hepatic venous pressures and hepatic artery blood flow were stable, and portal blood flow decreased slightly at very high propranolol levels. In seven dogs studied without dissection of the hepatic vessels, there was a small decrease in portal pressure, but not in wedged and free hepatic venous pressures with increasing doses of propranolol. Thus, in dogs with intrahepatic portal hypertension, propranolol has significant effects on systemic hemodynamics, but only minimal effects on the hepatic circulation.

Animals↗
PubMed1992

A prospective randomized trial comparing repeated endoscopic sclerotherapy and propranolol in decompensated (Child class B and C) cirrhotic patients.

A prospective randomized study was conducted to compare the efficacy of long-term endoscopic sclerotherapy vs. propranolol in Child class B and C patients with variceal bleeds within the 30 days before the study. Forty-five and 46 patients were randomized to receive sclerotherapy and propranolol, respectively, after preentry stratification for Child scores. Sclerotherapy was administered with 1% polidocanol at 10-day intervals until obliteration of varices was achieved. Propranolol was administered to achieve a reduction in resting pulse rate of 25%. Rebleeding occurred in 19 patients undergoing sclerotherapy and in 31 receiving propranolol (p less than 0.05). The number of episodes of rebleeding was higher (p less than 0.05) in the propranolol group (n = 64) than in the sclerotherapy group (n = 35). The mean bleeding risk factor, number of hospitalizations for rebleeding and blood transfusion requirement were also significantly higher in the propranolol-treated patients. The median bleed-free period was more than 36 mo in the sclerotherapy group and 2.5 mo in the propranolol group (p less than 0.01). The median survival time was significantly longer in the sclerotherapy group (greater than 36 mo) than in the propranolol group (greater than 24 mo). We conclude that in decompensated cirrhotic patients, long-term endoscopic sclerotherapy is superior to propranolol in preventing rebleeding and improving survival.

Adult↗