Plasma Propranolol Concentrations Research Articles

Assessment of Blood Collection Systems for the High Performance Liquid Chromatography Measurement of Propranolol

The effect of blood collection devices on the high performance liquid chromatography (HPLC) measurement of propranolol was assessed. Blood was collected from hypertensive patients treated with propranolol for at least 7 days. Two venipunctures (opposite arm technique) were performed on each patient using the reference (syringe/silanized, ethylene diamintetraacetate tubes) procedure and the Vacutainer Brand Tubes (lavender-, royal blue-, green-, and red-stoppered) that were free of tris(2-butoxyethyl) phosphate. Propranolol concentrations were determined utilizing a published HPLC procedure. This study showed that in the four evacuated tubes, propranolol concentrations in serum or plasma were highly correlated to those of the reference procedure (correlation coefficients, 0.986 to 0.997; and slope, 0.912 to 1.013). Mean propranolol concentrations of the red-stoppered tube serum were lower (7.5%) than that of the reference syringe (0.01 less than p less than 0.05). Thus, lavender-, royal blue-, green-, and red-stoppered tubes would be acceptable for propranolol monitoring.

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.

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.

Effects of cholestyramine and colestipol on the plasma concentrations of propranolol.

The effect of equivalent hypolipidaemic doses of cholestyramine (8 g) or colestipol (10 g) on the plasma concentrations of propranolol and 4'-hydroxypropranolol was studied in 12 normal volunteers following the oral administration of 120 mg of normal release propranolol tablets. When two doses of either cholestyramine or colestipol were administered prior to the propranolol, the peak plasma concentrations and area under the curve for both propranolol and the metabolite 4'-hydroxypropranolol were reduced significantly (P less than 0.05). We conclude that the drug interaction between cholestyramine or colestipol and propranolol leads to significant reductions in plasma concentrations of propranolol and 4'-hydroxypropranolol which may cause a clinically diminished effect for a given dosage. Therefore, patients should be observed when either of these resins are added to or deleted from a therapeutic regimen.

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.

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.

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.

Improved exercise tolerance after propranolol, diltiazem or nifedipine in angina pectoris: Comparison at 1, 3 and 8 hours and correlation with plasma drug concentration

Exercise tolerance 1, 3 and 8 hours after 80 mg of propranolol, 120 mg of diltiazem and 20 mg of nifedipine, and after 20 minutes of 0.6 mg of sublingual nitroglycerin were compared with placebo in 15 men who had chronic stable angina pectoris. Three hours after drug ingestion, the exercise time was prolonged by 72 ± 26, 162 ± 27 and 161 ± 30 seconds ( p < 0.05) for propranolol, diltiazem and nifedipine, respectively, and by 123 ± 35 seconds (p < 0.001) 20 minutes after sublingual nitroglycerin compared with placebo. The onset of ST-segment depression ≥ 0.1 mV was delayed by 120 ± 34, 203 ± 29 and 189 ± 35 seconds (p < 0.05) and by 79 ± 23 seconds (p < 0.05), respectively. After propranolol, the peak rate-pressure product decreased compared with placebo (15.1 ± 1.1 U [10 −3] vs 20.0 ± 1.5 U, p < 0.01). In contrast, the peak rate-pressure product was greater after diltiazem and nifedipine than after placebo (22.2 ± 1.3 U [p < 0.05] and 23.8 ± 1.4 U [p < 0.01]). The maximal increase in exercise tolerance was most marked for each drug at 3 hours, but was also significant at 1 hour for nifedipine and at 8 hours for diltiazem. At 3 hours, an increase in exercise time of more than 2 minutes was observed in 4 of 6 patients who had plasma propranolol concentrations > 40 ng/ml, 8 of 9 who had a plasma diltiazem concentration > 150 ng/ml, and in 7 of 7 who had a plasma nifedipine concentration > 90 ng/ml. Thus, in patients with chronic stable angina pectoris, propranolol decreases myocardial oxygen demand to a greater extent than diltiazem, nifedipine and nitroglycerin. Each drug increases exercise tolerance, although the timing of the antianginal effect of the drugs differ. Diltiazem showed a prolonged improvement in exercise tolerance up to 8 hours after administration.

Increased availability of propranolol in rats with uranyl nitrate-induced acute renal failure.

The effect of acute renal failure (ARF) on the pharmacokinetics of propranolol was investigated. The model of ARF was produced by the subcutaneous injection of uranyl nitrate to rats (10 mg/kg) and was used 3 d after treatment. Uranyl nitrate-treated rats showed significantly higher plasma concentrations of propranolol after oral administration and the area under the plasma concentration-time curve increased about 3-fold compared to control rats. The plasma disappearance of propranolol after intravenous administration did not differ significantly between control and ARF. The mean availability of propranolol after oral administration increased from 0.120 in control to 0.215 in ARF (p less than 0.005). Absorption of propranolol was almost complete and no significant difference was found between two groups. No changes in plasma protein binding of propranolol and hepatic blood flow were observed in ARF. On the other hand, hepatic clearance of propranolol determined by liver perfusion studies showed a significant reduction in ARF and the calculated intrinsic clearance of unbound propranolol at a dose of 6.25 mg was 26.8 +/- 2.3 ml/min in control and 16.0 +/- 2.3 ml/min in ARF (p less than 0.01). These results demonstrate that the oral availability of propranolol increased in ARF due to a reduction in the hepatic presystemic elimination as compared to healthy control rats.

Electrophysiologic actions of high plasma concentrations of propranolol in human subjects

The authors have previously shown that 40% of patients whose ventricular arrhythmias respond to propranolol require plasma concentrations in excess of those producing substantial beta-receptor blockade (greater than 150 ng/ml). However, the electrophysiologic actions of propranolol have only been examined in human beings after small intravenous doses achieving concentrations of less than 100 ng/ml. In this study, the electrophysiologic effects of a wider concentration range of propranolol was examined in nine patients. Using a series of loading and maintenance infusions, measurements were made at baseline, at low mean plasma propranolol concentrations (104 +/- 17 ng/ml) and at high concentrations (472 +/- 68 ng/ml). Significant (p less than 0.05) increases in AH interval and sinus cycle length were seen at low concentrations of propranolol, with no further prolongation at the high concentrations; these effects are typical of those produced by beta-blockade. However, progressive shortening of the endocardial monophasic action potential duration and QTc interval were seen over the entire concentration range tested (p less than 0.05). At high concentrations, there was significant (p less than 0.05) further shortening of both the QTc and monophasic action potential duration beyond that seen at low propranolol concentrations, along with a progressive increase in the ratio of the ventricular effective refractory period to monophasic action potential duration. No significant changes were seen in HV interval, QRS duration or ventricular effective refractory period. In summary, the concentration-response relations for atrioventricular conductivity and sinus node automaticity were flat above concentrations of 150 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Beta-adrenoceptor blocker intoxication: epidemiological data. Prenalterol as an alternative in the treatment of cardiac dysfunction.

1 During the three years 1978--1980 the Swedish Poison Information Centre received reports of 184 patients hospitalized due to beta-adrenoceptor blocker overdosage. Of the 35 patients who developed signs of severe cardiac dysfunction (HR less than 50 beats/min, systolic blood pressure less than 80 mm Hg), 23 had ingested propranolol, 10 metoprolol and 2 alprenolol. 2 The mean value of the defined daily doses (DDD) per 1000 inhabitants per day in Sweden during these years were 11.97 for propranolol, 8.02 for alprenolol and 7.74 for metoprolol. The incidence of severe poisoning due to alprenolol overdosage is lower than expected according to DDD. 3 During 1979 19 persons died from overdosage with beta-adrenoceptor blockers in Sweden: 15 due to propranolol (non-selective, lacks intrinsic sympathomimetic activity), 2 to metoprolol (cardioselective, lacks intrinsic sympathomimetic activity). These findings indicate that severe and even fatal poisoning may occur regardless of the type of beta-blocking agent. 4 The usefulness of prenalterol, a cardioselective beta-adrenoceptor partial agonist, in reversing unwanted cardiac effects of beta-adrenoceptor blocking agents is illustrated by two cases of massive propranolol intoxication (maximal plasma concentrations of propranolol 7.2 and 7.8 mumol/l respectively). Prenalterol in high doses (130 and 280 mg/24 h respectively) restored cardiac function.

Determination of propranolol and its major metabolite, naphthoxylactic acid, in human plasma by high performance liquid chromatography.

High performance liquid chromatography (HPLC) with a fluorometric detector was applied to the determination of propranolol and its major metabolite, naphthoxylactic acid (NLA), in human plasma following a single oral low dose (20 mg) of propra olol HCl. Propranolol and NLA were extracted successively from the sample aliquot. The carboxyl group of NLA was methylated with diazomethane in order to avaoid interference from blank plasma and a very strongly tailing peak on the HPLC chromatogram. The mean recoveries of propranolol and NLA subjected to the entire analytical protocol were better than 92%. The detection limits were 0.5 ng/ml for propranolol and 2 ng/ml for NLA. The calibration curves for propranolol HCl (20-100 ng/ml) and NLA (0.2-2 μg/ml), showed good linearity. The plasma concentrations of propranolol and NLA following a single oral administration of 20 mg of propranolol HCl to three healthy male subjects were determined by this method.

Comparative oral bioavailability of conventional propranolol tablets and a new controlled-absorption propranolol capsule

AbstractThe relative bioavailabilities of a new once-a-day propranolol formulation (Duranol) and conventional propranolol tablets (Inderal) were evaluated in six healthy male volunteers in a randomized balanced cross-over study. During the first treatment period, subjects were administered either a single 160 mg Duranol capsule at 9 a.m. or 80 mg Inderal at 9 a.m. and 9 p.m. Plasma propranolol concentrations were measured at 0, 2, 3, 4, 5, 6, 8, 10, 12, 13, 14, 15, 16, 24 and 36 hours after the 9 a.m. dose.Mean peak plasma propranolol concentrations (Cmax) of 92.7 ng/ml at 2 hours and 53.9 ng/ml at 2.8 hours were recorded after administration of the first and second Inderal doses, respectively. After Duranol dosing, the Cmax of 85 ng/ml was not significantly different than the Inderal values; however, Duranol's tmax of 8 hours was significantly greater (p < 0.05) than either tmax recorded for Inderal. Compared to data obtained after administration of conventional propranolol tablets, mean propranolol conc...

Urine and plasma propranolol.

Eight hypertensive patients who had been followed in an outpatient clinic during long-term therapy with propranolol (40 to 160 mg twice daily) were studied during a 24-hr stay in the ward. The usual oral dose was given and the total and free plasma concentrations were determined during the 24 hr and the urinary excretion of unchanged drug was measured. Average free plasma concentration of propranolol (y free) was calculated from: y free = Excreted propranolol (ng/24 hr)/Creatinine clearance (ml/24 hr). There was a significant relationship between log y free and average free plasma concentration (means free) determined from the directly measured plasma concentration curve: log y free = 0.0743 means free - 0.0466 (r = 0.98, P less than 0.001). In another group of propranolol-treated hypertensive patients there was a significant positive relationship between orosomucoid concentration and reciprocal of the free propranolol fraction in plasma. From this relationship the average total drug concentration (y total) was calculated from y free; there was a significant correlation with directly measured total plasma level: log y total = 0.0038 . means total + 1.0895 (r = 0.91, P less than 0.001). It is suggested that individually determined values of y free below 30 ng/ml and y total below 400 ng/ml (the concentration range studied) can be used to calculate the average mean 24-hr free and total plasma concentrations.

Increased Drug Effect Induced by Surgery

1 A thyrotoxic patient receiving a constant dose of propranolol and digoxin developed marked bradycardia postoperatively. 2 Compared to preoperative levels there was a considerable rise post-operatively in both plasma propranolol and serum digoxin steady-state concentrations. 3 Surgery by effecting drug disposition and disease processes may significantly alter drug handling in the perioperative period.

A bioequivalence study of three preparations of propranolol.

The bioequivalence of two different tablets and a solution, each containing 10 mg propranolol hydrochloride was studied in twelve healthy volunteers. Single oral doses of each preparation were administered at intervals of one week. Samples of blood for propranolol radioimmunoassay were taken up to 8 h after dosing. The plasma propranolol concentration at 0.5 h was significantly higher for the solution than for the two tablet formulations which did not differ significantly from each other at any sampling point. The area under the curve was similar for all three preparations. The study demonstrated that the three different preparations of propranolol were bioequivalent.

Propranolol in Children: Safety-Toxicity

Four hours after acute ingestion of 400 to 1,200 mg of propranolol by a healthy, 3-year-old boy, his plasma concentration of propranolol was 2,289 ng/ml. The only pharmacologic effect observed was a diminished heart rate response to crying and activity. In a second case, a 4-year-old boy on chronic propranolol therapy for renovascular hypertension had a hypoglycemic seizure when solid food was refused for three days because of an oral wound. The hypoglycemia was easily managed with intravenous glucose, and there were no sequelae. The first case alludes to the safety of propranolol in a healthy child even with very high plasma concentrations. The second case suggests the necessity of anticipating and avoiding hypoglycemia that can develop in children on chronic propranolol therapy when caloric intake is impaired.

The developing liver: the steady-state disposition of propranolol in pregnant sheep.

The steady-state disposition of the beta-adrenoreceptor blocking drug, propranolol, and its metabolite, 4-hydroxypropranolol, was studied in the anesthetized pregnant sheep near term. Following infusion of propranolol to the mother, steady-state plasma concentrations were obtained at three dosage levels in each of the eight animals studied. Blood samples were obtained from : (i) maternal facial artery and hepatic vein; (ii) umbilical vein, and (iii) fetal carotid artery, portal vein, and right hepatic vein. Although total propranolol concentrations in maternal plasma were different from those in umbilical venous plasma, the concentrations of unbound drug were similar, suggesting that unbound drug had equilibrated across the placenta. Approximately 10% of propranolol was unbound in maternal plasma, compared with 30% in fetal plasma. Hepatic extraction of propranolol by the maternal liver was high, so that only 3 to 4% of the drug presented to the liver escaped uptake. In contrast, fetal hepatic extraction was low. Negligible amounts were removed from portal vein blood (right lobe), although one third was extracted from umbilical vein blood (left lobe). Mean peripheral arterial concentrations of 4-hydroxypropranolol were 2- to 3-fold higher in the fetus than in the mother. We conclude that the fetus is exposed to significant concentrations of propranolol and that the fetal hepatic extraction of this drug is considerably less efficient than in the adult. In contrast to the adult liver, the fetal liver does not appear to act as a single homogeneous organ, but rather as two distinct subunits.