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PubMed1981

The distribution of propranolol, pindolol and atenolol between human erythrocytes and plasma.

1 This study aimed (1) to measure the whole blood to plasma (WB:P) and red blood cell to plasma (RBC:P) concentration ratios of propranolol in healthy volunteers and two types of patients, and (2) to compare the concentration ratios of the lipophilic drug propranolol with moderately lipophilic pindolol and hydrophilic atenolol. 2 There was no significant difference between the WB:P and RBC:P ratios of propranolol concentration in healthy volunteers and neurological patients compared with hypertensive patients. The mean +/- s.d. WB:P ratios of propranolol concentration in the three groups were 0.74 +/- 0.03, 0.71 +/- 0.05, and 0.76 +/- 0.08 respectively. The mean RBC:P ratios were 0.39 +/- 0.08, 0.36 +/- 0.11, and 0.47 +/- 0.15 respectively. WB:P and RBC:P concentration ratios of propranolol were linearly correlated with the free fraction of drug in plasma. Propranolol was 90% bound in plasma. 3 The mean WB:P and RBC:P ratios of pindolol in seven volunteers were 0.69 +/- 0.08 and 0.37 +/- 0.14 respectively. Pindolol was 71.4 +/- 8.6% bound to plasma proteins. The concentration of pindolol in the RBC was linearly correlated with that unbound in plasma. 4 In four healthy volunteers, the mean WB:P concentration ratio of atenolol was 1.07 +/- 0.25 and the mean RBC:P ratio was 1.15 +/- 0.55. 5 The similarity of the RBC:free plasma drug concentration ratios for all three drugs suggests that the use of organic solvent partition coefficients for the prediction of in vivo distribution may be unreliable.

Adolescent↗
PubMed1981

The influence of age, smoking and hyperthyroidism on plasma propranolol steady state concentration.

1 Plasma propranolol steady state concentration (Css) was determined during chronic dosage (160 mg/day) in 22 hyperthyroid patients (aged 16-75 years, 11 smokers, 11 non-smokers) and again following treatment when euthyroid. 2 There was a positive correlation between plasma propranolol Css and age in patients both when hyperthyroid (r = 0.74, P less than 0.01) and when euthyroid (r = 0.58, P less than 0.05). 3 Plasma propranolol Css in hyperthyroid patients were lower (P less than 0.05) in smokers than in non-smokers. 4 Following correction of hyperthyroidism there was a significant increase (P less than 0.01) in both the plasma propranolol Css and degree of plasma protein binding of propranolol. 5 Hyperthyroidism and smoking are known to increase the rate of drug metabolism and it is suggested that these variables may give rise to or accentuate an age related reduction in propranolol clearance.

Adolescent↗
PubMed1982

The acute and chronic effect of oxprenolol and propranolol on peripheral blood flow in hypertensive patients.

1 The effects of oxprenolol and propranolol on peripheral blood flow were compared in patients with mild and moderate essential hypertension. 2 In an acute double-blind crossover study in which eight patients participated there was a significant reduction in resting forearm blood flow (RFBF) 2 h after 80 mg propranolol (mean +/- s.e. mean) (-0.87 +/- 0.13 microliter min-1 100 g-1) and after 80 mg oxprenolol (-0.30 +/- 0.12) but not after placebo. This reduction was significantly greater after propranolol (P = 0.022). 3 Seven patients continued into a double-blind crossover study comparing the above dose of the two drugs twice a day. On both the beta-adrenoceptor blockers there was a significant reduction in blood pressure after 2 weeks of treatment and also a significant reduction in RFBF. 4 After 6 weeks treatment with propranolol the reduction in RFBF persisted and was significantly less (P = 0.04) than after 6 weeks treatment of oxprenolol, at which time RFBF was back to control. 5 There were no consistent changes in skin temperature. 6 Neither propranolol nor oxprenolol should be used in patients with severe peripheral vascular disease. 7 If beta-adrenoceptor blockade is necessary in patients with mild peripheral vascular disease oxprenolol should be used in preference to propranolol but should be prescribed with caution.

Adult↗
PubMed1983

Changes in heart rate and forearm blood flow following intravenous boluses of isoprenaline in the presence of practolol and propranolol.

1 Increases in heart rate and forearm blood flow following graded intravenous bolus injections of isoprenaline sulphate, were measured in a double-blind randomised study of six subjects who received either placebo, practolol 50 mg, practolol 200 mg, propranolol 10 mg or propranolol 40 mg. 2 Dose related increases in forearm blood flow were produced by the graded boluses of isoprenaline sulphate. 3 Practolol 50 mg attenuated the heart rate response to isoprenaline but did not significantly affect the changes in forearm blood flow. Practolol 200 mg further attenuated the heart rate responses but also decreased the forearm blood flow responses. 4 Propranolol 10 mg and propranolol 40 mg significantly attenuated both the heart rate and forearm blood flow responses. The effect on forearm blood flow tended to be greater than the effect on heart rate. 5 Practolol 200 mg had the same effect on heart rate responses as propranolol 10 mg but a significantly smaller effect on the forearm blood flow responses. 6 The measurement of forearm blood flow following intravenous bolus injections of isoprenaline provides useful information about the beta 2-adrenoceptor antagonism of propranolol and practolol. However, application of the technique may be limited by the magnitude of the heart rate response and by the short-lived nature of the increase in forearm blood flow.

Adult↗
PubMed1983

Heart rate and blood pressure responses to intravenous boluses of isoprenaline in the presence of propranolol, practolol and atropine.

Six healthy subjects were studied on two occasions. Graded bolus injections of isoprenaline sulphate were given intravenously and control dose-response curves were drawn for the changes in heart rate and blood pressure. In a random order each subject received an intravenous infusion of either propranolol or practolol and further dose-response curves were constructed PRE- and POST-atropine (0.04 mg/kg). Exercise tachycardia was reduced 26.1 +/- 2.7% by propranolol and this was not significantly different from the reduction by practolol (21.2 +/- 1.9%). Propranolol attenuated the isoprenaline tachycardia (dose ratio 43.7) and after atropinisation the dose ratio was not significantly altered (41.1). Practolol also attenuated the isoprenaline tachycardia (dose ratio 4.4) but after atropinisation the dose ratio was significantly increased to 8.8, though this remained significantly less than the dose ratio for propranolol. At a heart rate increase of 25 beats/min, the isoprenaline-induced control fall in mean blood pressure was 9-11 mm Hg. After propranolol administration this fall was converted to a small increase of + 2.3 +/- 1.3 mm Hg. Following practolol, however, the mean blood pressure reduction was 19.7 +/- 2.9 mm Hg. Practolol did not significantly block the isoprenaline-induced fall in diastolic pressure. The difference in potency of propranolol and practolol, demonstrated by their effect on isoprenaline induced tachycardia at doses shown to have equal effects on exercise tachycardia, is contributed to but not fully explained by the reflex withdrawal of cardiac vagal tone which occurs with cardioselective but not non-selective antagonists.

Adrenergic beta-Antagonists↗
PubMed1984

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.

Adult↗
PubMed1984

Central effects of single oral doses of propranolol in man.

The central effects of propranolol, a lipophilic beta-adrenoceptor antagonist, were investigated in six healthy male volunteers using two flash fusion threshold (2FFT), simple reaction time (SRT), digital copying test (DCT), symbol digit modalities test (SDMT), Gibson spiral maze test (GSMT) and mood rating scales for tension, alertness, depression, detachment and anxiety. Compared to placebo, 2FFT was prolonged by propranolol 40, 80 and 160 mg at one or more times tested but not by propranolol 320 mg: the largest effect was seen at 3 h after 40 mg, and the effects of 40, 80 and 160 mg were significantly greater than 320 mg at 2 h. SRTs were significantly prolonged by all doses of propranolol at 2 and 3 h and by 40 and 80 mg doses at 5 h. DCT was lowered by 40 and 80 mg at 2 and 3 h by 80 mg at 5 h, and by 320 mg at 2 h, but the 160 mg dose had no effect. Propranolol impaired the expected retest gain of the SDMT with all doses except 320 mg and at 2 h after 40, 80 and 160 mg, performance was actually worsened. Mood rating scales showed increased detachment with 40 mg and decreased alertness with 80 and 320 mg. The results show that propranolol has central effects in man: the effects appeared to be greater with lower doses, 40 and 80 mg, than with higher doses, 160 and 320 mg.

Adult↗
PubMed1986

Partial metabolic clearances as determinants of the oral bioavailability of propranolol.

The objective of this study was to determine the relationships between the total oral clearance of propranolol and the partial clearances through its primary metabolic pathways, i.e. glucuronidation, side-chain oxidation and ring oxidation. Seven young, white males were given single 80 mg oral doses of the drug together with tritium-labelled propranolol. Plasma propranolol was measured by GC/MS and fourteen metabolites were measured in urine by h.p.l.c. with radiometric detection. The total oral clearance of propranolol in these subjects varied about three-fold, from 27.5 to 71.4 ml min-1 kg-1. The clearance through glucuronidation was very similar in all subjects, ranging from 6.8 to 9.9 ml min-1 kg-1. The clearance through side-chain oxidation varied 2.4-fold, from 10.9 to 25.8 ml min-1 kg-1. Increased clearance through this pathway correlated with increased total oral clearance (r = 0.84; P less than 0.02). The clearance through ring oxidation varied as much as 5.6-fold, from 7.5 to 41.8 ml min-1 kg-1. Increased clearance through this pathway correlated highly with increased total oral clearance (r = 0.94; P less than 0.002). These observations indicate that the intersubject variability in the oral clearance of propranolol in young, white males is due mainly to differences in the activity of the ring oxidation pathway, to some extent in the side-chain oxidation pathway, but not to differences in the glucuronidation pathway. The partial metabolic clearance approach adopted in this study may be useful in the investigation of factors influencing the oral bioavailability of propranolol.

Administration, Oral↗
PubMed1988

Nonlinear accumulation of propranolol enantiomers.

The accumulation of (+)- and (-)-propranolol was investigated in nine subjects who received 160 mg of racemic propranolol as a single dose and then once daily for 7 days. The serum concentrations of propranolol enantiomers were measured by h.p.l.c. using a novel chiral stationary phase allowing direct resolution of underivatized propranolol. The (+)-propranolol AUC increased from 412 +/- 223 ng ml-1 h after single doses (0-infinity) to 584 +/- 279 ng ml-1 h at steady-state (0-24 h) (P less than 0.05). Similarly, (-)-propranolol AUC increased from 609 +/- 304 to 777 +/- 370 ng ml-1 h (P less than 0.05). The AUC ratio (-)/(+) was 1.52 +/- 0.36 and 1.32 +/- 0.17 after single doses and steady-state, respectively (P greater than 0.05). Therefore, nonlinear accumulation occurs with both enantiomers although there is a trend for the (-)/(+) ratio to decrease at steady-state.

Adult↗
PubMed1989

Pharmacokinetic and pharmacodynamic comparison of two doses of long acting propranolol (80 and 160 mg) in healthy subjects.

1. The kinetics and dynamics of long acting propranolol 80 mg and 160 mg were examined after single oral doses to 12 healthy volunteers. 2. Long acting propranolol 160 mg produced a twofold increase in mean peak blood propranolol concentration and AUC compared with the lower dose. There was no difference in elimination half-life, bioavailability and mean residence time of propranolol between the two doses. 3. Resting pulse rate was decreased by long acting propranolol 160 mg but not by the lower dose. 4. Both preparations blocked exercise induced tachycardia during the entire observation period of 29 h. Percentage inhibition of exercise tachycardia was significant at all time points but long acting propranolol 160 mg exhibited a greater reduction at 24 h and 29 h. 5. Increase in systolic blood pressure during exercise was inhibited by both preparations during the entire observation period with no differences between them. 6. The doubling of the dose administered was reflected in blood concentrations but not in pharmacodynamic parameters. Few pharmacodynamic differences were found between the two doses.

Adult↗
PubMed1989

Pharmacokinetic and pharmacodynamic interactions between the ACE inhibitor cilazapril and beta-adrenoceptor antagonist propranolol in healthy subjects and in hypertensive patients.

1. Six healthy subjects received cilazapril (2.5 mg once daily), propranolol (120 mg once daily), the combination of both and placebo for a period of 1 week each (wash-out phase 1 week). 2. Propranolol and cilazapril reduced systolic and diastolic blood pressure (BP) by 7 mm Hg at peak when compared with placebo. However after the combination, this reduction was more than doubled (18 mm Hg) and lasted longer. 3. There was a trend to lower and later peak concentrations for both drugs after administration of the combination. No clinically relevant pharmacokinetic interactions between cilazapril and propranolol were found. 4. The effects on blood pressure were confirmed in hypertensive patients (BP diastolic greater than 95 mm Hg). Thirteen patients were randomly allocated cilazapril (2.5 mg day-1) or propranolol (120 mg day-1] as part of a cross-over design. This was then followed by the combination. All treatment periods were of 3 weeks duration and all measurements were done 2 h after drug administration. 5. Cilazapril lowered the median sitting diastolic BP by 8 mm Hg, and propranolol by 9 mm Hg, whereas the combination reduced the diastolic BP by 19 mm Hg. 6. The results of these studies, attempting to elucidate drug-drug interactions, showed that combined use of propranolol and cilazapril resulted in a more pronounced and longer lasting blood pressure reduction, in healthy subjects and in patients with hypertension.

Adult↗
PubMed1989

Comparison of the cardiovascular and pulmonary effects of oral celiprolol, propranolol and placebo in normal volunteers.

1. The effects on heart rate, blood pressure and pulmonary function of single oral doses of celiprolol hydrochloride (400 mg), and propranolol (40 mg) were compared with placebo in 12 healthy volunteers, in a double-blind three-period crossover study. 2. Celiprolol had no effect on heart rate while propranolol caused a significant reduction compared with placebo. Systolic blood pressure was reduced by propranolol but not celiprolol, whereas standing diastolic blood pressure was lowered by both drugs. 3. The maximal expiratory flow at 50% vital capacity (MEF.50), was significantly lower after propranolol compared with placebo and celiprolol. Celiprolol had no effect on the flow-volume loop parameters. 4. Effective pulmonary blood flow was significantly increased by celiprolol, but reduced by propranolol. 5. A high incidence of subjective side-effects were experienced on celiprolol (10/12; particularly unpleasant in 5). Side-effects were experienced to a lesser extent on placebo (8/12). Only one volunteer experienced a side-effect on propranolol. 6. Oral celiprolol exerts its hypotensive effect by vasodilatation without reflex tachycardia. It does not cause airways obstruction in healthy subjects.

Adrenergic beta-Antagonists↗
PubMed1991

Lack of an interaction between propranolol and sumatriptan.

1. The effect of twice-daily dosing with propranolol on the pharmacokinetics and pharmacodynamics of a single oral dose of sumatriptan was investigated in 10 healthy male subjects. 2. Each subject received 7 days dosing with propranolol (80 mg twice daily) plus a single dose of sumatriptan (300 mg orally) on day 7; on another separate occasion, placebo was administered for 7 days plus a single dose of sumatriptan on day 7. There was at least a 7 day washout interval between the two periods of dosing. Pulse and blood pressure were measured up to 10 h after dosing with sumatriptan and blood samples were taken up to 26 h post-dose. 3. Propranolol had no significant effect on any of the derived pharmacokinetic parameters of sumatriptan. The appropriate average parameter values in the presence of propranolol were, respectively: Cmax (120 ng ml-1 vs 126 ng ml-1), tmax (4.5 h vs 3.0 h), AUC (580 ng ml-1 h vs 566 ng ml-1 h), t 1/2,z (1.9 h vs 1.8 h). 4. Propranolol had no significant effect on the pharmacodynamics of sumatriptan, as measured by pulse rate and blood pressure. 5. The results of this study would suggest that no alteration in the sumatriptan dosage will be necessary for migraine patients taking propranolol prophylactic therapy.

Adult↗
PubMed1994

Trimetazidine: a new concept in the treatment of angina. Comparison with propranolol in patients with stable angina. Trimetazidine European Multicenter Study Group.

1. Trimetazidine has a direct anti-ischaemic effect on the myocardium without altering the rate x pressure product or coronary blood flow. 2. The effects of trimetazidine (20 mg three times daily) were compared with those of propranolol (40 mg three times daily) in a double-blind parallel group multicentre study in 149 men with stable angina. 3. Reproducibility of exercise performance was verified during a 3 week run-in placebo washout period. All patients had > 1 mm ST-depression on exercise test. 4. After 3 months, similar anti-anginal efficacy was observed between the trimetazidine (n = 71) and propranolol (n = 78) groups. No significant differences were observed between trimetazidine and propranolol as regards anginal attack rate per week (mean difference P-TMZ: 2; 95% CI: -4.4, 0.5) and exercise duration (mean difference P-TMZ: 0 s; 95% CI: -33, 34) or time to 1 mm ST segment depression (mean difference P-TMZ: 13 s; 95% CI: -24, 51). Heart rate and rate x pressure product at rest and at peak exercise remained unchanged in the trimetazidine group but significantly decreased with propranolol (P < 0.001 in all cases). With both drugs there was a trend to decreased ischaemic episodes in the 46% patients who experienced ambulatory ischaemia on Holter monitoring. Six patients stopped trimetazidine and 12 propranolol. Of these, five in each group were withdrawn because of deterioration in cardiovascular status. 5. The results suggest that trimetazidine and propranolol at the doses studied have similar efficacy in patients with stable angina pectoris.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗
PubMed1982

Propranolol improves the impaired TSH response to TRH in patients with autonomously functioning euthyroid multinodular goitre.

Ten patients with autonomously functioning euthyroid multinodular goitre received propranolol (Inderal Retard 160 mg daily) for 4 weeks in order to investigate whether normalization of the TRH test or an increased TSH response to TRH could be obtained by decreasing serum T3 levels. Serum T3 decreased significantly after 2 and 4 weeks of propranolol administration. Serum T4 increased during this period, although the change was only significant after 4 weeks of propranolol. T3 resin uptake did not change. The TSH response to TRH increased significantly during the administration of propranolol. Mean delta TSH basally was 1.0, range 0-3.9 mU/l, and mean delta TSH after 4 weeks of propranolol was 2.4, range 0-9.3 mU/l. A strong correlation was found between the increase in delta TSH and the decrease in serum T3 after 4 weeks of propranolol. After withdrawal, delta TSH and T3 returned to premedication levels. Our data suggest that T3 is an important factor in the impairment of the TSH response to TRH in our patients. Normalization of the TRH test was, however, not obtained. These findings support the concept of subclinical hyperthyroidism in 'euthyroid' multinodular goitre with autonomous function.

Adult↗
PubMed1990

The effect of D- versus L-propranolol in the treatment of hyperthyroidism.

The purpose of this study is to determine whether there is a difference in treatment of hyperthyroidism using either the D- or L-isomer of propranolol. Two groups of 20 patients with overt hyperthyroidism received either 120 mg L- or D-propranolol each for a period of 5 days. In the D-propranolol administered group there was a significant decrease in TT3 and fT3 plasma levels and in the ratio of TT3 to TT4; however, a significant increase occurred in rT3 values up to day 5. On the other hand, L-propranolol treatment resulted in a less pronounced decrease in TT4 and TT3 values, while all other thyroid hormone levels remained unchanged as, above all, did the T3/T4 ratio. The well known effect of D,L-propranolol upon peripheral conversion of T4 to T3 is thus not due to the beta-blocking action of L-propranolol but is mainly conditioned by the D-isomer which has no beta-blocking action itself.

Adult↗
PubMed1996

Divergent effects of propranolol and nadolol in isolated mesenteric arteries from normal and portal hypertensive rats.

Propranolol, a non-selective beta-blocker, is used for treatment of portal hypertension as it is believed to diminish splanchnic blood flow both by reducing cardiac output (beta(1)-blockade) and by increasing splanchnic arteriolar resistance (beta(2)-blockade). However, possible vasodilatory properties of propranolol at higher concentrations may counteract splanchnic vasoconstriction. Nadolol, another nonselective beta-blocker, has also been suggested for treatment of portal hypertension. The aim of the present study was to investigate the effects of various concentrations of propranolol and nadolol on vascular resistance in isolated perfused mesenteric arterial beds from normal and portal hypertensive rats. At concentrations of 10(-7) mol L-1 to 10(-6) mol L-1 neither propranolol nor nadolol changed pressor responses to noradrenaline in normal rats. However, nadolol 10(-5) mol L-1 significantly increased, whereas propranolol 10(-5) mol L-1 reduced, noradrenaline-induced vasoconstriction both in normal and in portal hypertensive rats. This unexpected vasodilatory effect of propranolol at high concentrations was present in preparations stimulated by both noradrenaline and methoxamine but not vasopressin and thus may be due to competitive alpha-receptor blockade. In contrast, nadolol lacked this effect and produced splanchnic arteriolar vasoconstriction at high concentrations also.

Adrenergic beta-Antagonists↗
PubMed1991

A sensitive high-performance liquid chromatographic analysis of propranolol in serum.

A rapid and sensitive high-performance liquid chromatographic (HPLC) assay was developed for quantitative determination of propranolol in serum. The assay is performed after single extraction of propranolol and indenolol [internal standard (IS)] from alkalinized serum into ether and eluted from C-18 U Bondapak column with a mobile phase composed of methanol: 0.01 M phosphate buffer pH 3.4 (40:60%, v/v). The column eluant was monitored on a fluorescence detector. Measurement was achieved by taking the peak height ratio of propranolol and comparing it to that of the IS. The detection limit for propranolol in serum is 2.5 ng/ml. Intraday coefficients of variation (CV) ranged from 2.84 to 4.0% and interday (CVs) from 5.8 to 8.4% at three different concentrations. The relative and absolute recoveries varied from 93.8 to 102.3%. Preliminary stability tests showed that propranolol is stable for at least 3 weeks in serum after freezing. The method is applied for the determination of the pharmacokinetic parameters of propranolol after intravenous administration (1 mg/kg) to rabbits.

Animals↗