Plasma Propranolol Research Articles

Decreased bioavailability of propranolol due to interactions with adsorbent antacids and antidiarrhoeal mixtures

The interaction of propranolol (50–160 mg/100 ml) with recommended doses of magnesium trisilicate, kaolin-pectin and bismuth subsalicylate suspensions was studied. Magnesium trisilicate and bismuth subsalicylate were found to adsorb propranolol with a limiting adsorptive capacity of 112 and 97 mg/g, respectively. Kaolin-pectin suspension adsorbed practically all of the drug. The effect of these interactions on the bioavailability of propranolol in rats was determined. The extent, but not the rate. of propranolol absorption was decreased on concomitant administration of the adsorbents. Peak propranolol plasma concentrations decreased by 2924̄5% and a parallel decrease of 35–44% in AUC values was observed. These interactions suggest possible clinically important differences in propranolol bioavailability.

Hemodynamic and metabolic effects of the calcium channel blocking agent nitrendipine

In an open crossover comparison of propranolol and nitrendipine, 19 patients with hypertension received 40 to 160 mg propranolol and 5 to 20 mg nitrendipine twice a day. Mean (+/- SD) predose supine blood pressure fell from 145/98 +/- 11/7 to 132/88 +/- 12/8 mm Hg with propranolol and to 135/92 +/- 11/9 mm Hg with nitrendipine. Resting heart rate was reduced by propranolol but was unchanged 12 hours after nitrendipine dosing. Neither propranolol nor nitrendipine altered plasma glucose or insulin after oral glucose. Propranolol significantly increased fasting triglyceride levels and reduced high-density lipoprotein cholesterol levels, but nitrendipine induced no change. Propranolol reduced and nitrendipine increased plasma renin activity after exercise. Peak plasma nitrendipine levels were dose proportional and occurred at 1 to 2 hours after dosing, whereas peak blood pressure reductions occurred 4 hours after the last dose of nitrendipine and were associated with mean increases in heart rate. Nitrendipine is almost equivalent in hypotensive effect to propranolol, but nitrendipine increases plasma renin activity after exertion and may produce transient tachycardia. However, nitrendipine does not cause unwanted metabolic effects.

In support of cardiac chronotropic beta 2 adrenoceptors

The effects of atenolol (50 mg) and propranolol (40 mg) on exercise- and isoproterenol-induced heart rate increments were studied in 9 male volunteers. Propranolol reduced maximal heart rate from 187 ± 4 to 146 ± 7 beats/min and atenolol reduced it to 138 ± 6 beats/min. There was no difference between the drugs at any point during exercise. Isoproterenol sensitivity was measured as the dose of isoproterenol required to increase resting heart rate by 25 beats/min (CD-25). Propranolol increased the CD-25 from 1.8 ± 0.3 μg after placebo to 39 ± 8 μg and atenolol increased the CD-25 to 8 ± 2 μg. The increase by propranolol was significantly greater than that of atenolol. Intravenous atropine (0.04 mg/kg) did not alter the isoproterenol CD-25 during placebo or atenolol. The CD-25 with propranolol decreased after atropine (39 ± 8 versus 25 ± 5 μg) and was due to diminished plasma propranolol concentrations as the drug sensitivity (measured by Ka) was unchanged before (12 ± 2 ml/ng) and after (10 ± 3 ml/ng) atropine. These data support the hypothesis that moderate exercise is primarily a β 1-mediated response and therefore equally antagonized by cardioselective and nonselective blockers, but that isoproterenol stimulates both β 1 and β 2 receptors. The greater ability of the nonselective agent to antagonize isoproterenol tachycardia with no significant change after atropine suggests the presence of cardiac β 2 chronotropic receptors. The physiologic and pathologic importance of these receptors has yet to be determined.

Quantitative determination of propranolol in plasma and plasma water from normal subjects and patients with angina pectoris by high-performance liquid chromatography

A precise and sensitive high-performance liquid chromatographic method using a column packed with porous polystyrene gel is described for the determination of propranolol in plasma and plasma water from normal subjects and patients with angina pectoris. Propranolol in the samples was extracted with an n-heptane—isoamylalcohol (98.5:1.5) mixture after addition of penbutolol used as an internal standard. The extracts were chromatographed and detected with a spectrofluorophotometer. The quantitative limit of propranolol was 1 ng using 1 ml of plasma or 0.5 ml of plasma water. The present method should be useful for monitoring propranolol concentrations in plasma and plasma water during drug therapy and for pharmacokinetic study of propranolol.

Determination of the new β-blocker bisoprolol and of metoprolol, atenolol and propranolol in plasma and urine by high-performance liquid chromatography

High-performance liquid chromatographic methods using fluorimetric detection have been developed for the determination in plasma and urine of bisoprolol, atenolol, metoprolol and propranolol. Bisoprolol, metoprolol and propranolol were extracted at alkaline pH with dichloromethane, atenolol with n-butanol—dichloromethane (25:75). After evaporation of the organic solvent the compounds were chromatographed on silica gel Si-60 columns (normal phase) using aqueous ammonium phosphate buffer (pH 4) containing 3–7% acetonitrile as eluent (method 1). Alternatively, the compounds were acetylated prior to chromatography on reversed-phase columns (RP-8), using acetonitrile—water mixtures as eluents (method 2). The detection limit was 1–2 ng/ml in plasma and 10 ng/ml in urine for bisoprolol and metoprolol with either method. For atenolol the detection limit was 5 ng/ml in plasma or 50 ng/ml in urine (method 1), for propranolol 1 ng/ml in plasma (method 2).

Short-term effects of propranolol on portal venous pressure.

The present study was designed to investigate the effect of propranolol on portal pressure of patients with alcoholic cirrhosis and portal hypertension and to correlate these effects with clinical and laboratory parameters. The mean baseline hepatic venous pressure gradient in the 50 patients studied was of 18.2 +/- 4.1 mm Hg. It decreased significantly 2 hr after the oral administration of 40 mg of propranolol to 15.7 +/- 4.2 mm Hg (a mean reduction of 13.4 +/- 17%). This reduction in hepatic venous pressure gradient resulted mainly from a decrease in mean wedged hepatic venous pressure. There was no correlation between the decrease in hepatic venous pressure gradient and the decrease in heart rate. When results were analyzed individually, only 15 (30%) showed a large decrease in hepatic venous pressure gradient (greater than 20%), 15 (30%) showed a moderate decrease (10 to 19%), and in 20 patients (40%) there was no reduction or an increase in hepatic venous pressure gradient. Comparison of "responders" (those that reduced hepatic venous pressure gradient greater than 10%) and "nonresponders" (hepatic venous pressure gradient reduction less than 10%) showed no significant differences in baseline laboratory and hemodynamic parameters, in the severity of the liver disease, in the heart rate and blood pressure response to propranolol, nor in the propranolol plasma levels achieved 2 hr after propranolol administration. Propranolol plasma levels correlated with the reduction in heart rate but not with the reduction in hepatic venous pressure gradient. Of 14 nonresponders to 40 mg of propranolol who received additional doses, six showed a reduction in hepatic venous pressure gradient.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of propranolol in plasma by radial compression liquid chromatography with fluorometric detection.

This radial compression liquid-chromatographic assay for propranolol in plasma is rapid, reproducible, and suitable for use in routine monitoring. A 10-micron particle, 8 mm X 10 cm CN cartridge is used in conjunction with a radial compression separation system. The mobile phase is monobasic sodium phosphate (pH 3) solution/methanol/acetonitrile (760/84/156 by vol), the flow rate 6 mL/min. Propranolol was detected by use of a spectrofluorometer equipped with a 20-microL flow-through cell, at excitation and emission wavelengths of 250 and 336 nm. The retention times for propranolol and metoprolol (the internal standard) are 3.13 and 1.42 min, respectively. A one-step extraction with chloroform yields "clean" chromatograms, with greater than 90% of the drug being analytically accounted for. Under these conditions, results are precise and accurate. Currently we are using this method to monitor propranolol in hypertensive neonates. Data on changes in the concentrations of propranolol in plasma with time are presented for one such patient.

Effect of age on the hepatic clearance of propranolol in rats.

The effect of age on hepatic clearance of propranolol was investigated in male Wistar rats (3 to 104 weeks old). Pharmacokinetic analysis of the plasma propranolol data obtained after i.v. dosage (1.0 mg kg-1) indicated that both the elimination rate constant and the volume of distribution decreased with age between weeks 5 and 11, after when the distribution volume remained almost constant. The elimination rate constant was reduced consistently with age after 15 weeks. Total body clearance of the drug was reduced extensively with age between weeks 5 and 11 (94 to 43 ml min-1 kg-1) and decreased gradually thereafter. The plasma free fraction of propranolol also decreased with age, falling from more than 20% in 3 to 5 weeks-old rats to about 10% in rats of 52 to 104 weeks. In immature rats the renal clearance was approximately 5 to 12% of the total body clearance. Intrinsic hepatic clearance for unbound propranolol also decreased with age between weeks 7 and 24. As expected from the evidence that propranolol has a high extraction ratio, the extent of its hepatic clearance was significantly dependent on the liver blood flow. These data suggest that the age-dependent decrease in hepatic clearance of propranolol is largely due to a reduction of the elimination rate that might be accompanied by the age-dependent decrease in liver blood flow.

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

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

Plasma concentration-response relationships of two formulations of propranolol.

The time-course of beta blockade induced by two formulations of propranolol was compared to their plasma concentration-time curves. Graded infusions of isoproterenol were used to assess the degree of beta blockade at different times after oral administration of 80 mg of propranolol to 11 healthy volunteers. The time-course of drug effect was measured as the decline of the systolic pressor dose 20 (SPD 20) and the chronotropic dose 20 (CD 20). Variability of plasma propranolol concentration was small, varying within subjects from 27% to 36% and between subjects from 19% to 28% at the various sampling times. Pharmacodynamic effects showed a similar reproducibility: intra-individual variation was 15% to 28% for CD 20 and 17% to 32% for SPD 20; interindividual variation was 10% to 24% for CD 20 and 13% to 23% for SPD 20. Pooling of the data of all subjects indicated a parallel decline of drug concentration and effect. However, three of the 11 subjects showed drug effects declining at a faster rate than drug levels. This dissociation between serum concentrations and effects points out the clinical relevance of complementing kinetic studies of propranolol with pharmacodynamic studies. The good reproducibility within subjects and the small interindividual variation suggests that isoproterenol dose-response curves may be a useful tool for such studies.

Combination propranolol and bepridil therapy in stable angina pectoris

The safety and efficacy of bepridil plus propranolol therapy were investigated in a placebo-controlled, parallel-design, double-blind trial in 56 patients who were not responding to propranolol alone. Patients entering the study were receiving an average propranolol dosage of 131 mg/day (range 20 to 240). For the first 2 weeks of the study they were given placebo in addition to their propranolol dose, and then were randomized to receive continued placebo plus propranolol or bepridil plus propranolol therapy. The bepridil dosage was adjusted over the 8 weeks of active treatment to an average of 273 mg/day (range 200 to 400). The double-blind treatment period was followed by a 3-week washout period during which all patients received propranolol and placebo. The effects of treatment on the frequency of angina attacks, nitroglycerin consumption, exercise performance (treadmill-modified Bruce protocol) and Holter electrocardiogram (ECG) were assessed. Propranolol and bepridil plasma levels also were obtained. Improved antianginal efficacy and reduced nitroglycerin consumption were noted when bepridil was added to propranolol (p < 0.01). During 8 weeks of combination treatment, exercise tolerance increased 1.0 ± 1.2 minutes from a baseline of 7.3 ± 2.2 with bepridil plus propranolol compared with an increase of 0.02 ± 1.3 minutes from a baseline of 7.6 ± 2.9 with placebo plus propranolol (p < 0.01). With bepridil plus propranolol, there were also increases in exercise time to onset of angina (p < 0.04), exercise time to 1-mm electrocardiographic ST-segment depression (p < 0.06) and total work (p < 0.03) compared with placebo plus propranolol therapy. Resting heart rate was reduced a maximum of 2 beats/min with combination treatment compared with propranolol alone, and no differences in blood pressure between treatment groups were observed. There were no clinically significant rhythm changes on Holter ECG with combination treatment, and bepridil treatment had no effect on plasma propranolol levels. Bepridil did prolong the QTc interval on resting ECG by a mean of 37 ± 39 millisecond. Adverse effects were mild with bepridil plus propranolol and greater in frequency than those with placebo plus propranolol. With cessation of bepridil, patients returned toward the angina frequency and exercise tolerance levels seen at baseline with propranolol alone. The addition of bepridil to propranolol provided safe and effective antianginal therapy in patients whose angina was not controlled by propranolol alone.

Assay of total and free propranolol in plasma by liquid chromatography with fluorometric detection.

We report a liquid-chromatographic method for assay of total and free propranolol and its metabolite, propranolol glycol, in plasma. An ultrafiltration device is used to separate the free drugs from the protein-bound drugs. The total and free drugs are isolated from plasma or ultrafiltrate by liquid-solid extraction on a Waters C18 SEP-PAK and the drugs are quantified on a C18 mu-Bondpak radial-compression column. The mobile phase consists of equal parts of methanol and a solution of potassium 50 mmol/L phosphate and 2.5 mmol/L 1-pentane-sulfonic acid, pH 5.0. Detection was by fluorescence, with excitation at 296 nm and emission at 338 nm. Time required for sample preparation for total-propranolol assay is 40 min per eight samples. Sample preparation for free-propranolol assay requires an additional 1 h per eight samples. Chromatography requires 15 min per sample. The extraction recovery is approximately 75% and the assay curve is linear from 5 to 400 micrograms/L. The run-to-run CV is 4% for total propranolol, 15% for free propranolol.

Pharmacology of propranolol in patients with cirrhosis and portal hypertension.

Ten patients with cirrhosis and protal hypertension received an initial 20 mg oral test dose of propranolol and subsequently 160 mg of a slow release preparation, orally, each day for seven days. Protein binding, serial plasma propranolol concentrations and effects on heart rate were studied. Protein binding was slightly reduced (mean 85%, range 78.9-88.1%) compared with four normals (mean 87.9%). In patients with severe liver disease (serum albumin less than 30 g/l) propranolol remained detectable in plasma 24 hours after the single 20 mg dose and high steady state concentrations (mean 266.5 ng/ml, range 84-406) were observed during regular dosing. At steady state there was a significant correlation between log total plasma propranolol concentrations and the percentage fall in heart rate (r = 0.659, p less than 0.05). We suggest that in patients with severe liver chronic disease (serum albumin less than 30 g/l), propranolol therapy should be initiated in hospital. The starting dose should be low (20 mg of the conventional formulation tds or 80 mg of the slow release preparation daily) and that regular monitoring of the heart rate should be carried out.

Propranolol concentrations in blood serum, seminal plasma and saliva in man after a single oral dose.

A single dose of 80 mg racemic propranolol hydrochloride was administered by mouth to six healthy male volunteers. The mean concentration achieved in seminal plasma at 2 h after dosing was almost identical to that in blood serum. The concentrations of propranolol in seminal plasma and saliva were much less than those known to reduce sperm motility by 50% in vitro. The concentrations in saliva did not reflect those in blood serum. Propranolol in the dose administered in this study is unlikely to affect fertility by its presence in saliva or semen.

Polymorphic ability to metabolize propranolol alters 4-hydroxypropranolol levels but not beta blockade.

The ability to hydroxylate debrisoquine is known to be polymorphically distributed, with about 8% to 9% of the North American Caucasian population being poor metabolizers. We have shown that the ability to 4-hydroxylate propranolol is also polymorphically determined and that it cosegregates with ability to metabolize debrisoquine, such that poor debrisoquine metabolizers produce much less 4-hydroxypropranolol (4-OH propranolol) than do extensive metabolizers. There was no significant difference, however, between plasma propranolol concentrations after either single or multiple doses in the two groups. Despite the substantial difference in production of the pharmacologically active 4-OH metabolite, no difference was seen in the extent of beta-blockade induced in the extensive and poor metabolizers, which implies that 4-OH propranolol does not contribute substantially to beta-blockade.

Antihypertensive effect and degree of beta-adrenoceptor blockade after short-term and semi-chronic propranolol therapy.

In patients with normal-renin, mild (n = 6) or moderate (n = 6) hypertension, the antihypertensive effects of propranolol (80 mg/day) for 1 day or for 2 weeks were evaluated in relation to the degree of beta-adrenoceptor blockade induced. A significant and similar fall in systolic blood pressure was observed after 1 day and 2 weeks on propranolol in both groups of patients. In contrast, diastolic blood pressure showed only a minor decrease after 1 day of therapy (-2 +/- 2 and -3 +/- 1 mm Hg) but a significant drop (-7 +/- 3 and -9 +/- 3 mm Hg) after 2 weeks in the mild and moderate hypertension groups, respectively. Plasma propranolol levels and decreases in resting heart rate and PRA were similar after 1 day and 2 weeks of treatment. Isoprenaline dose-response curves for systolic and diastolic blood pressure, heart rate and PRA showed similar parallel shifts after 1 day and 2 weeks of treatment. The effect of graded bicycle exercise on these parameters were also similarly blunted. These results indicate that over time, systolic blood pressure decreases rapidly whereas diastolic blood pressure shows a delayed fall following initiation of low-dose propranolol therapy, despite the same degree of beta-adrenoceptor blockade.

Assessment of beta-adrenergic blockade with propranolol in patients with cirrhosis.

Fourteen patients with cirrhosis and bleeding esophageal varices were treated with propranolol. The dose of propranolol was determined by decreasing the resting heart rate by 25% 12 hr after an oral dose of propranolol which was given twice a day. Significant decreases in the hepatic venous pressure gradient and cardiac output after 1 month of propranolol administration was observed. To assess beta-adrenergic blockade, the isoproterenol test and plasma propranolol levels were evaluated. Increasing doses of isoproterenol were injected to increase the resting heart rate 25 beats per minute (chronotropic dose 25 or CD25 ). Plasma propranolol concentrations were measured in blood samples drawn 4 hr after the last oral dose. The mean CD25 was 5 +/- 2 micrograms before and 146 +/- 84 micrograms after 1 month of propranolol administration. The plasma propranolol level after 1 month of drug administration was 0.69 +/- 0.47 microM per liter i.e. 2.33 +/- 1.59 micrograms per ml. A significant correlation was found between the CD25 measured after continuous propranolol administration and plasma propranolol level. In conclusion, the efficacy of beta-adrenergic blockade was estimated by the isoproterenol test which correlates with the plasma propranolol level in patients with cirrhosis. This study suggests that the isoproterenol test is useful in assessing beta-adrenergic blockade with propranolol in patients with cirrhosis.

Kinetic interactions of nadolol and propranolol with cimetidine.

British Journal of Clinical PharmacologyVolume 17, Issue 4 p. 486-487 Free Access Kinetic interactions of nadolol and propranolol with cimetidine. KL Duchin, KL DuchinSearch for more papers by this authorMA Stern, MA SternSearch for more papers by this authorDA Willard, DA WillardSearch for more papers by this authorDN McKinstry, DN McKinstrySearch for more papers by this author KL Duchin, KL DuchinSearch for more papers by this authorMA Stern, MA SternSearch for more papers by this authorDA Willard, DA WillardSearch for more papers by this authorDN McKinstry, DN McKinstrySearch for more papers by this author First published: April 1984 https://doi.org/10.1111/j.1365-2125.1984.tb02379.xCitations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References Feely, J., Wilkinson, G. R. & Wood, A. J. J. (1981). Reduction of liver blood flow and propranolol metabolism by cimetidine. New Engl. J. Med., 304, 692– 695. Funke, P. T., Malley, M. F., Ivashkiv, E. & Cohen, A. I. (1978). Determinations of serum nadolol levels by GLC-selection monitoring mass spectrometry: comparison with a spectrofluoro-metric method. J. pharm. Sci., 67, 653– 657. Gibaldi, M. & Perrier, D. (1982). Pharmacokinetics. New York: Marcel Dekker, Inc. Kirch, W., Spahn, H., Kohler, H., Ohnhaus, E. E. & Mutschler, E. (1982). Interactions of metoprolol, propranolol, and atenolol with concurrent administration of cimetidine. Klin. Wochenschr., 60, 1401– 1407. Pelkonen, O. & Puurunen, J. (1980). The effect of cimetidine on in vitro and in vivo microsomal drug metabolism in the rat. Biochem. Pharmac., 29, 3075– 3080. Reimann, I. W., Klotz, U., Siems, B. & Frohlich, J. C. (1981). Cimetidine increases steady-state plasma levels of propranolol. Br. J. clin. Pharmac., 12, 785– 790. Shand, D. G., Nuckolls, E. M. & Oates, J. A. (1970). Plasma propranolol levels in adults with observations in four children. Clin. Pharmac. Ther., 11, 112– 120. Citing Literature Volume17, Issue4April 1984Pages 486-487 ReferencesRelatedInformation

Changes in blood chemistry in hypertensive patients during propranolol therapy.

Propranolol induced changes in blood plasma chemistry were followed in thirty hypertensive patients (WHO I-II) who were seen each week during 14-15 weeks. The initial 4 weeks were a drug free period and the next 2 weeks were a drug adjustment period. After that the patients were on an unchanged propranolol dose for 8 weeks (40, 80 or 160 mg four times daily). For all observed changes the correlation was studied to (1) dose, (2) free and total simultaneously determined plasma concentration and (3) free and total average plasma concentration of unchanged drug during the preceding 24 h period. Total protein and albumin did not change significantly. After 4 and 8 weeks on the final dose orosomucoid was increased significantly (by 10%) compared with the value from the end of the drug free period. Creatinine rose significantly during the initial 4-6 weeks therapy to remain at the same level during the last 4 weeks. Urate was increased at the two lowest dose levels. Total cholesterol fell significantly (5%) while triglycerides increased significantly (16%). T4 rose significantly, T3 fell and r-T3 rose significantly in a dose dependent way. Interindividually r-T3 was the only biochemical change showing a significant relationship to the propranolol plasma concentration. The relationship reached the highest level of significance to the average 24 h free concentration.

The interaction of cigarette smoking and beta-adrenoceptor blockade.

The importance of the interaction between smoking and propranolol (metabolised in the liver) and atenolol (excreted almost entirely in the urine) was investigated in a double-blind placebo-controlled trial. Resting and exercise heart rates were significantly greater during smoking than no-smoking phases. Atenolol and propranolol significantly improved ST segment response after exercise whether or not the patients were smoking. Plasma propranolol significantly increased when patients stopped smoking whereas there was no such change in atenolol levels.