Single Oral Doses Of Propranolol Research Articles

Study of effect of propranolol, atenolol and celiprolol on exercise induced changes in heart rate, blood pressure and peak expiratory flow rate in healthy human volunteers

Background: Beta blockers are known to cause attenuation of sympathetic stimulation mediated increase in cardiovascular parameters. Very few studies are available in Indian set-up comparing these changes between different beta blockers available in market. The objective of the study was to compare efficacy and safety of propranolol, atenolol and celiprolol on heart rare, blood pressure and airway resistance, both at rest and during exercise.Methods: A prospective interventional study was carried out involving 72 healthy volunteers in the clinical pharmacology laboratory. Participants were divided in three groups of 24 each and given single oral doses of propranolol 40 mg, Atenolol 50 mg and celiprolol 40 mg was given to the participants. Exercise given in the form of step ladder test and hand grip dynamometer and effect on the different parameters like HR, SBP, DBP and PEFR were recorded before and immediately after exercise and compared.Results: All the three drugs were effective in attenuating the exercise induced cardiovascular parameters (p <0.05). Drug A cause change in HR, SBP, DBP and PEFR significantly (p <0.05). Change in SBP was more significant with drug B while significant difference was found in HR, SBP and DBP before and after exercise in drug C in both SL and HGD tests. No significant difference was found between the drug groups (p >0.05). No adverse effects were reported in the study participants.Conclusions: All the three drugs are effective in attenuating cardiovascular changes after sympathetic stimulation like exercise and there was no significant difference among them.

Beta-Adrenergic Modulation of Tremor and Corticomuscular Coherence in Humans

Coherence between the bioelectric activity of sensorimotor cortex and contralateral muscles can be observed around 20 Hz. By contrast, physiological tremor has a dominant frequency around 10 Hz. Although tremor has multiple sources, it is partly central in origin, reflecting a component of motoneuron discharge at this frequency. The motoneuron response to ∼20 Hz descending input could be altered by non-linear interactions with ∼10 Hz motoneuron firing. We investigated this further in eight healthy human subjects by testing the effects of the beta-adrenergic agents propranolol (non-selective β-antagonist) and salbutamol (β2-agonist), which are known to alter the size of physiological tremor. Corticomuscular coherence was assessed during an auxotonic precision grip task; tremor was quantified using accelerometry during index finger extension. Experiments with propranolol used a double-blind, placebo-controlled crossover design. A single oral dose of propranolol (40 mg) significantly increased beta band (15.3–32.2 Hz) corticomuscular coherence compared with placebo, but reduced tremor in the 6.2–11.9 Hz range. Salbutamol (2.5 mg) was administered by inhalation. Whilst salbutamol significantly increased tremor amplitude as expected, it did not change corticomuscular coherence. The opposite direction of the effects of propranolol on corticomuscular coherence and tremor, and the fact that salbutamol enhances tremor but does not affect coherence, implies that the magnitude of corticomuscular coherence is little influenced by non-linear interactions with 10 Hz oscillations in motoneurons or the periphery. Instead, we suggest that propranolol and salbutamol may affect both tremor and corticomuscular coherence partly via a central site of action.

Induction of Propranolol Metabolism by Ginkgo biloba Extract EGb 761 in Rats

Ginkgo biloba is one of the most popular herbal medicines in the world, due to its purported pharmacological effects, including memory-enhancing, cognition-improving, and antiplatelet effects. When used in the elderly, Ginkgo has a high potential for interactions with cardiovascular drugs. This study aimed to investigate the effects of the standard Ginkgo biloba extract (EGB 761) treatment on the pharmacokinetics of propranolol and its metabolism to form N-desisopropylpropranolol (NDP) in rats. We also examined the activity and expression of cytochrome P450 (CYP) 1A and other CYPs in rats treated with EGb 761 at 10 and 100 mg/kg/day for 10 days. A single oral dose of propranolol (10 mg/kg) was administered on day 11 and the concentrations of both propranolol and NDP were determined using validated liquid chromatography-mass spectrometry (LC-MS) methods. The levels of mRNA and protein of various CYPs were determined by RT-PCR and Western blotting analysis, respectively. Pretreatment of EGb 761 at 100 mg/kg, but not 10 mg/kg, for 10 days significantly reduced the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of propranolol, whereas those values of NDP were significantly increased. CYP1A1, 1A2, 2B1/2, and 3A1 activities and gene expression in the rat liver were significantly increased in a dose-dependent manner by pretreatment with EGb 761. The ex-vivo formation of NDP in liver microsomes from rats pretreated with EGb 761 was markedly enhanced. The formation of NDP from propranolol in liver microsomes was significantly inhibited by alpha-naphthoflavone (ANF, a selective CYP1A2 inhibitor), but not by quinidine (a CYP2D inhibitor). These results indicated that EGb 761 pretreatment decreased the plasma concentrations of propranolol by accelerated conversion of parental drug to NDP due to induction of CYP1A2. EGb 761 pretreatment also significantly induced CYP2B1/2 and CYP3A1, suggesting potential interactions with substrate drugs for these two enzymes. Further study is needed to explore the potential for gingko-drug interactions and the clinical impact.

Effect of piperine on bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers

The effect of piperine on the bioavailability and pharmacokinetics of propranolol and theophylline has been examined in a crossover study. Six subjects in each group received a single oral dose of propranolol 40 mg or theophylline (150 mg) alone or in combination with piperine 20 mg daily for 7 days. An earlier tmax and a higher Cmax and AUC were observed in the subjects who received piperine and propranolol. It produced a higher Cmax, longer elimination half-life and a higher AUC with theophylline. In clinical practice, the enhanced systemic availability of oral propranolol and theophylline could be exploited to achieve better therapeutic control and improved patient compliance.

The effects of propranolol or atenolol on the cardiovascular responses to central hypovolaemia in Europeans and Bengalees.

1. The effects of single oral doses of propranolol (80 mg), or atenolol (100 mg) on resting heart rate, blood pressure, forearm blood flow and forearm vascular resistance and on responses to central hypovolaemia, were compared with those of placebo in nine healthy European and nine healthy Bengalee volunteers, in a double-blind, three-period, cross-over study. 2. Atenolol induced a significant reduction in resting systolic blood pressure (SBP) in Europeans but not in Bengalees, although the bradycardic effects of atenolol were similar in both groups. Atenolol did not have any significant effect on forearm blood flow (FBF) or forearm vascular resistance (FVR) in either group. In the presence of propranolol (80 mg) there were no statistically significant falls in BP but there were significant bradycardias, falls in FBF and rises in FVR that were similar in Europeans and Bengalees. 3. In the presence of placebo Europeans exhibited significant falls in diastolic blood pressure (DBP) during lower body negative pressure (LBNP) of 20 and 30 mm Hg. Bengalees did not show falls in DBP during LBNP. However, there were no significant differences between DBP responses in Europeans and Bengalee subjects. Both Bengalees and European subjects showed similar reductions in FBF and FVR during LBNP of 30 mm Hg. 4. In the presence of propranolol, significant changes in forearm blood flow and forearm vascular resistance were evident in Bengalee subjects during LBNP of 20 mm Hg and 30 mm Hg, whereas in the Europeans significant changes in those variables did not occur at any level. The changes in FBF and FVR during LBNP of 20 and 30 mm Hg in Bengalee and European subjects were significantly different.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of propranolol on exercise induced tachycardia is determined by plasma concentration and the density of adrenergic receptors on leukocytes.

The chronotropic response to a single oral dose of propranolol in 23 healthy subjects has been related to the plasma propranolol concentration and the density of beta-adrenoceptors on peripheral polymorphonuclear leucocytes. The percentage reduction in exercise-induced tachycardia was significantly correlated with the log plasma propranolol concentration within subjects but not between subjects. Taking the concentration of the active metabolite 4-hydroxypropranolol into account did not improve the interindividual correlation. The reduction in exercise-induced tachycardia was significantly correlated with the maximum binding density of (125I)-hydroxybenzylpindolol on polymorphonuclear leucocyte membrane fragments measured before medication. A response index (% reduction in exercise-induced tachycardia/plasma propranolol concentration) was correlated with the maximum binding density of (125I)-hydroxybenzylpindolol (pre-drug) at 2 h (rs = 0.72), 4 h (rs = 0.84) and 6 h (rs = 0.73) after dosing. The data suggest that interindividual variation in the response to propranolol after a single oral dose is determined by interindividual differences both in plasma propranolol and adrenoceptor density.

Variability in amplitude of untreated essential tremor.

Tremor amplitude was monitored in untreated patients with essential tremor by a procedure designed to minimise fluctuations due to factors known to influence tremor. Tremor was measured hourly for 6 hours in 14 patients and on five to seven occasions (separated by at least a week) in 22 patients. A wide range of within-patient variability was found, with some patients showing little and others showing considerable fluctuations in amplitude over the series of recordings. There was no simple relationship between variability and mean amplitude, frequency, age, duration of tremor or response to a single oral dose of propranolol. Variability did not differ between males and females or between patients with and without a family history of tremor. Diurnal fluctuations showed no consistent pattern. Long-term assessment revealed a significant trend towards lower amplitudes on successive occasions. To overcome systematic bias in data collection, clinical trials in essential tremor should employ large numbers of patients and rigorous randomisation of treatments in cross-over designs.

Increased clearance of propranolol and theophylline by high-protein compared with high-carbohydrate diet

The objective of this study was to determine whether changes in dietary protein and carbohydrate influence the oral clearance of propranolol, a high-clearance drug, and theophylline, a low-clearance drug. Six normal subjects studied in a clinical research center each received a single oral dose of propranolol, 80 mg, and theophylline, 5 mg/kg, after having been on each of two well-defined diets for a period of 10 days. When the diet was altered from high carbohydrate/low protein to low carbohydrate/high protein, the oral clearance of propranolol increased by 74% +/- 20% (mean +/- SE; range 9% to 156%; P less than 0.01) with no change in plasma half-life or plasma binding. This dietary change resulted in an increase in theophylline clearance of 32% +/- 6% (range 18% to 50%; P less than 0.02) and a corresponding decrease in plasma half-life of 26% +/- 6% (range 6% to 42%; P less than 0.05) with no alteration in the apparent volume of distribution. These observations reemphasize the importance of diet in drug disposition and suggest that the clearance of high-clearance drugs like propranolol is more susceptible than the clearance of low-clearance drugs to dietary manipulations, effects that may have to be considered in drug therapy.

Time course of a single oral dose of propranolol in essential tremor

Time course of a single oral dose of propranolol in essential tremor

Time course of a single oral dose of propranolol in essential tremor.

We studied the effects of a single oral dose (120 mg) of propranolol on essential tremor in 12 patients. Postural hand tremor was recorded by an accelerometer, and its amplitude and frequency determined by spectral analysis. Variable patterns of individual responses gave a mean reduction of tremor amplitude of 50% at 2 hours. Tremor was suppressed as long as 8 hours in some patients. Similar tremor reduction was found on chronic therapy. Even without treatment, tremor amplitude varied from 30 to 50%. A single oral dose of propranolol produces a rapid and sustained reduction of essential tremor, but there are diurnal fluctuations of tremor intensity regardless of treatment.

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.

Effect of dose and uremia on plasma and urine profiles of propranolol metabolites.

The relationship between plasma levels of 4 propranolol metabolites--naphthoxylactic acid (NLA), 4-hydroxypropranolol (4-OH), naphthoxyacetic acid (NAA), and propranolol glycol (PG)--and propranolol plasma levels was determined in healthy, adult male subjects after increasing single oral doses of propranolol. NLA was present at plasma levels 6 to 25 times that of propranolol. More than 90% of circulating NLA was in the plasma fraction, where it was 95% protein bound. The ratio of plasma concentrations of the pharmacologically active metabolite 4-OH to propranolol approached unity 0.5 hr after propranolol, 160 mg or 320 mg orally, but fell rapidly. Plasma levels of NAA were in the same range as propranolol, especially as time progressed. PG circulated at plasma levels less than 12% of propranolol. As oral doses of propranolol were increased from 20 to 320 mg, there was a decrease in intrinsic plasma clearance (Cli) from 425 to 200 1/hr. Half-life rose from 3 to 5 hr. Urinary recovery of 4-OH fell as Cli rose. Urinary recovery of propranolol conjugates, NLA, and N-desisopropylpropranolol (NDIPP) rose as Cli fell. Our results suggest that naphthalene ring oxidation of propranolol represents a high-affinity low-capacity enzymatic pathway(s) that plays an important role in the extensive hepatic extraction of propranolol after small doses orally. Plasma NLA and plasma NAA were determined before and after hemodialysis in 14 uremic patients receiving long-term propranolol therapy. Mean plasma NLA was 4.372 ng/ml, and mean plasma NAA level was 238 ng/ml when mean plasma propranolol level was 15 ng/ml.

Beeinflussung des Augeninnendruckes des Augengesunden nach Einnahme von Propranolol und Metoprolol

Oral doses of propranolol and metoprolol were tested on 24 patients without glaucoma. The aim of this study was to compare the decrease in intraocular pressure in normal eyes following a single oral dose of propranolol or metoprolol. A statistically significant decrease in IOP was noticed, but no difference was seen between propranolol and metoprolol.

Selectivity of beta adrenoreceptor antagonist drugs assessed by histamine bronchial provocation

In a double-blind, within-patient, randomized study, 12 mild asthmatics were given single oral doses of propranolol (80 mg), metoprolol (100 mg), timolol (10 mg), or placebo. Resting heart rate and forced expiratory volume in one sec (FEV1) were measured before and 90 min after treatment. Nonspecific bronchial reactivity was measured by inhaled histamine at 90 min. Following each active drug, resting heart rate changed to a similar extent and to a greater degree than after placebo (p less than 0.01). Changes in FEV1 were small and not different from those after placebo. In contrast, after each active drug, bronchial reactivity increased more than after placebo. The degree of reactivity with each active drug was similar but the differences from corresponding placebo values were significant (p less than 0.05). We conclude that, in mild asthmatics, nonspecific bronchial reactivity is a more sensitive index of airway effects than resting FEV1. Moreover, in the context of this study, since the beta-blockers were given in doses likely to induce equivalent cardiac beta-blockade, there is no evidence to suggest that any one of them is more "cardioselective" than the others.

The effects of propranolol, practolol and metoprolol on exercise-induced tachycardia in relation to plasma levels in man.

1. The effects of single oral doses of propranolol, practolol and a new cardioselective beta-adrenoceptor blocking drug, metoprolol, on exercise-induced tachycardia in relation to plasma levels were studied in six normal volunteers. 2. Exercise undertaken on treadmill was submaximal which, under control conditions, increased the heart rate from 74-3 (s.e.m. = 6-8) to 153-8 (s.e.m. = 9.8) beats/min. 3. Plasma concentrations of propranolol and practolol were assayed fluorometrically and of metoprolol by electron-capture gas liquid chromatography, the details of which are described. 4. Between 1-5 and 2 h after drug ingestion 80 mg of propranolol associated with plasma level of 50-60 ng/ml (half-life 2-75 h), reduced the exercise-induced tachycardia by 27%, 250 mg of practolol with plasma levels of 1050-1100 ng/ml reduced it by 28% and 100 mg of metoprolol with plasma concentrations of 140-150 ng/ml (half-life 1-7 h), reduced it by 30%. 5. The resting heart rates were reduced significantly by propranolol and metoprolol but not by practolol. 6. Metoprolol is a potent short-acting beta-adrenoceptor antagonist; its advantages as a cardioselective agent over practolol in therapeutic use are discussed.

NARCOTIC WITHDRAWAL SYMPTOMS IN HEROIN USERS TREATED WITH PROPRANOLOL

Propranolol, a β-adrenergic blocking agent, is useful in the treatment of heroin addiction. It prevents the euphoric effects of heroin; in addicts from whom heroin is withdrawn it eliminates, or much reduces, the distressing and enduring residual craving for the narcotic; and it is a non-narcotic, non-addicting, and relatively safe drug that is effective when given orally in small doses. Propranolol taken in the usual amounts does not help in the management of the acute physical withdrawal symptoms. Two cases are described in which heroin, self-administered after the use of propranolol, actually precipitated, without accompanying euphoric effects, major symptoms of withdrawal. In one case the symptoms occurred after a single oral dose of propranolol 10 mg. given for the first time in the course of a double-blind trial of this medication, and persisted for twenty-four hours despite further use of heroin. In the other case, they were subsequently reactivated for twenty-four hours by further medications with propranolol; the adverse reaction led to a request for continued treatment with propranolol as a prophylactic against recurrent use of heroin.

Effect of propranolol on the response of serum growth hormone to glucagon.

ABSTRACT In normal subjects the response of serum growth hormone to the intramuscular or subcutaneous injection of glucagon was augmented by a single oral dose of propranolol (40 mg) given 2 hours before injection. In addition, propranolol induced a normal response of serum growth hormone to glucagon in the few normal persons failing to respond to glucagon alone. Although approximately 90% of normal persons respond to glucagon alone with a rise in serum growth hormone, oral propranolol increases the percentage and thus enhances the value of the glucagon stimulation test in detecting a deficiency of growth hormone. This conclusion is reinforced by the lack of response in hypopituitarism and the conversion of a poor to a normal response in 1 of 2 patients with primary hypothyroidism when propranolol was added to the glucagon stimulation test.