Long-acting Propranolol Research Articles

Propranolol Combined With Reactivation Therapy May Reduce PTSD Symptoms

Back to table of contents Previous article Next article PsychopharmacologyFull AccessPropranolol Combined With Reactivation Therapy May Reduce PTSD SymptomsNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:2 Feb 2018https://doi.org/10.1176/appi.pn.2018.pp2a2AbstractPropranolol may interfere with the reconsolidation of traumatic memories brought forth during the reactivation session, thus making them less potent and fear-inducing.It would be a tremendous breakthrough in treating posttraumatic stress disorder (PTSD) if patients were able to rid themselves of unwanted traumatic memories. Researchers and clinicians once believed that weakening memories might be an impossible task; however, studies over the past decade have found that when stored memories are retrieved, or reactivated, they temporarily enter a malleable state. Once a person stops thinking about a memory, the memory returns to a stable form, a process known as reconsolidation. iStock/laflorA drug that interferes with the reconsolidation of a reactivated traumatic memory could potentially weaken or even erase the retrieved memory. A study published January 12 in AJP in Advance suggests that the beta-blocker propranolol might be able to block memory reconsolidation.Adults with PTSD who actively recalled their traumatic event under the influence of propranolol once a week, for up to six weeks, reported a substantial decrease in PTSD symptoms compared with participants who took placebo. This decrease was evident from both the perspective of the patient and clinician.“The effect sizes obtained for pre-reactivation propranolol in our study compare well to those obtained with the best evidence-based treatment for PTSD, namely, cognitive-behavioral therapy, as well as those obtained with the most recommended pharmacological treatment for PTSD, namely, SSRIs,” Alain Brunet, Ph.D., an associate professor of psychiatry at McGill University in Montreal, and colleagues wrote. “Should these results be replicated in further studies, propranolol blockade of reconsolidation may become a new therapy for some patients with PTSD.”At the start of the six-week, double-blind, randomized trial, adults who had experienced at least six months of PTSD symptoms were assigned to take either propranolol (administered as 0.67 mg/kg of short-acting propranolol plus 1.0 mg/kg of long-acting propranolol) or placebo one hour before a brief memory reactivation session.Patients were excluded from the trial if they had a basal systolic blood pressure <100 mmHg; a basal heart rate <55 beats per minute; a medical condition contraindicating administration of propranolol or potentially confounding the results, such as arrhythmia or congestive heart failure; or were currently using medication that may interact adversely with propranolol, such as antiarrhythmic medications or calcium channel blockers. Three people in each group reported side effects after receiving the placebo or propranolol and were excluded from the rest of the trial.During the reactivation session, the participants were asked to write a one-page trauma narrative, focusing on the most disturbing moments of the traumatic event and including five or more bodily sensations drawn from a checklist. The participants were then asked to read the narrative aloud once to the therapist “as if they were back in the event.” At subsequent weekly visits, participants again took propranolol or placebo and were asked to re-read the narrative 90 minutes after they took their medicine.The participants filled out the patient-rated PTSD Checklist Specific (PCL-S) scale at the beginning of each treatment session, before propranolol or placebo was administered. The Clinician-Administered PTSD Scale (CAPS) was also used one week before and one week after the six-week trial.Both the propranolol and placebo groups had similar PCL-S and CAPS scores at baseline. At the end of the study participants who took propranolol had greater decreases in both measurements that were statistically significant. Pre- to post-treatment CAPS improvements were 38 percent in the propranolol group and 24 percent in the placebo group, while PCL-S improvements were 56 percent in the propranolol group and 15 percent in the placebo group. The investigators also conducted a six-month follow-up and found that the participants in the propranolol group continued to experience lower symptom scores than the placebo group, even without continued use of propranolol. However, the authors noted that the follow-up data only included 14 participants. “Further studies should make efforts to retain a greater percentage of participants for long-term follow-up,” the authors wrote.The patients in this study underwent trauma reactivation but did not receive full exposure therapy. Exposure therapy is a commonly used PTSD treatment that seeks to extinguish the link between a memory and the negative behaviors it elicits. While both therapies involve coaching the patient to relive a past traumatic event in some manner, the exposure component of reconsolidation therapy is kept to a maximum of about 25 minutes. This study was supported by a grant from the U.S. Army Congressionally Directed Medical Research Program. ■Back to Psychopharmacology Newsletter Table of Contents ISSUES NewArchived

β-Blocker therapy ameliorates hypersplenism due to portal hypertension in children.

Thrombocytopenia due to hypersplenism precludes percutaneous liver biopsy in many cases of chronic liver disease (CLD). The aim of this study was to assess the efficacy of propranolol in correcting platelet counts (>100,000/mm(3)) to ensure percutaneous liver biopsy in children with CLD. From January 2005 to December 2012, 51 consecutive children (mean age 11.5 ± 3.0 years, 34 boys) with CLD who needed liver biopsy but could not be done due to hypersplenism-related thrombocytopenia (platelets <100,000/mm(3) and/or total leukocyte counts <4,000/mm(3) with splenomegaly) were recruited and given a 4-week trial of long-acting propranolol (1.5-2 mg/kg/day). Hemodynamic parameters and splenic artery hemodynamics by Doppler ultrasound were recorded before and after the propranolol trial. Response to therapy was defined as improvement of platelet counts to ≥10(5)/mm(3). Thirty-two (62.7%) children responded to propranolol therapy and their mean platelet counts increased from 57.5 ± 13.0 × 10(3) to 140.7 ± 43.3 × 10(3)/mm(3), p = 0.0001. Liver biopsy could be done in 29. While comparing responders with non-responders, baseline spleen size (7.4 ± 3.3 vs. 12.7 ± 4.5 cm, p = 0.0001) and platelet counts (57.5 ± 13.0 × 10(3) vs. 39.5 ± 14.5 × 10(3), p = 0.0001) were found to be significant. ROC curve suggested a cut-off value of ≤8.5 cm of spleen and ≥53,000 platelets as predictors of response. With propranolol, mean arterial pressure and spleen size reduced (p < 0.05) and splenic artery resistance increased significantly (p = 0.005) in responders. Propranolol corrects thrombocytopenia and makes liver biopsy possible in almost two-thirds of cases by reducing splenic sequestration through splenic artery vasoconstriction. The baseline spleen size and platelet counts determine the effectiveness of therapy. A trial of β-blocker is worth carrying out in cases where liver biopsy is contraindicated due to hypersplenism-related thrombocytopenia.

Treatment of essential tremor: a systematic review of evidence and recommendations from the Italian Movement Disorders Association

Essential tremor (ET) is one of the most common movement disorders of adults, characterized by postural and kinetic tremor. It often causes embarrassment and more rarely serious disability, requiring treatment. To assess the current state of knowledge on ET therapy and produce recommendations based on the analysis of evidence the authors reviewed the literature regarding pharmacologic and surgical therapies, providing a quality assessment of the studies and the strength of recommendations for each treatment. A committee of experts selected clinical-based questions to guide the search. A systematic literature review was performed to identify all the studies conducted on patients with ET published until September 2010. Articles were classified according to GRADE evidence profile, a system for grading the quality of evidence and the strength of recommendation based on the quality of the studies. The quality of evidence was often rated as "low" or "very low" for the studies analyzed. Propranolol, long-acting propranolol, primidone, and topiramate are recommended as first-line therapy, with restrictions for their side effects. Arotinolol, sotalol, ICI 118.551 and LI 32.468 (experimental drugs), zonisamide, gabapentin, alprazolam, clozapine, and olanzapine are recommended as a second-line treatment. Botulinum toxin type A and thalamic deep-brain stimulation are recommended for refractory ET. The results highlight the need of well-designed direct comparison trials aimed at evaluating relative effectiveness and safety of the drugs currently used in clinical practice. Furthermore, additional controlled clinical trials are required to define other possible treatment strategies for ameliorating the management of ET.

Effect of Acute Posttrauma Propranolol on PTSD Outcome and Physiological Responses During Script‐Driven Imagery

Animal and human research suggests that the development of posttraumatic stress disorder (PTSD) may involve the overconsolidation of memories of a traumatic experience. Previous studies have attempted to use pharmaceutical agents, especially the β-adrenergic blocker propranolol, to reduce this overconsolidation. In this randomized, placebo-controlled study of the efficacy of propranolol in reducing the development of PTSD, we optimized dosages and conducted both psychophysiological and clinical assessments 1 and 3 months after the traumatic event. Forty-one emergency department patients who had experienced a qualifying acute psychological trauma were randomized to receive up to 240 mg/day of propranolol or placebo for 19 days. At 4 and 12 weeks post-trauma, PTSD symptoms were assessed. One week later, participants engaged in script-driven imagery of their traumatic event while psychophysiological responses were measured. Physiological reactivity during script-driven traumatic imagery, severity of PTSD symptoms, and the rate of the PTSD diagnostic outcome were not significantly different between the two groups. However, post hoc subgroup analyses showed that in participants with high drug adherence, at the 5-week posttrauma assessment, physiological reactivity was significantly lower during script-driven imagery in the propranolol than in the placebo subjects. The physiological results provide some limited support for a model of PTSD in which a traumatic conditioned response is reduced by posttrauma propranolol. However, the clinical results from this study do not support the preventive use of propranolol in the acute aftermath of a traumatic event.

Aspirin, but not propranolol, attenuates the acute stress-induced increase in circulating levels of interleukin-6: A randomized, double-blind, placebo-controlled study

Psychosocial stress might increase the risk of atherothrombotic events by setting off an elevation in circulating levels of the proinflammatory cytokine interleukin (IL)-6. We investigated the effect of aspirin and propranolol on the responsiveness of plasma IL-6 levels to acute psychosocial stress. For 5 days, 64 healthy subjects were randomized, double-blind, to daily oral aspirin 100 mg plus long-acting propranolol 80 mg, aspirin 100 mg plus placebo, long-acting propranolol 80 mg plus placebo, or placebo plus placebo. Thereafter, all subjects underwent the 13-min Trier Social Stress Test, which combines a preparation phase, a job interview, and a mental arithmetic task. Plasma IL-6 levels were measured in blood samples collected immediately pre- and post-stress, and 45 min and 105 min thereafter. The change in IL-6 from pre-stress to 105 min post-stress differed between subjects with aspirin medication and those without ( p = 0.033; η p 2 = 0.059). IL-6 levels increased less from pre-stress to 105 min post-stress ( p < 0.027) and were lower ( p = 0.010) at 105 min post-stress in subjects with aspirin than in subjects without aspirin. The significance of these results was maintained when controlling for gender, age, waist-to-hip ratio, mean arterial blood pressure, and smoking status. Medication with propranolol was not significantly associated with the stress-induced change in IL-6 levels. Also, aspirin and propranolol did not significantly interact in determining the IL-6 stress response. Aspirin but not propranolol attenuated the stress-induced increase in plasma IL-6 levels. This suggests one mechanism by which aspirin treatment might reduce the risk of atherothrombotic events triggered by acute mental stress.

Optimizing delivery systems to tailor pharmacotherapy to cardiovascular circadian events.

The role of chronotherapeutics--agents that match drug delivery to the natural circadian rhythms of the cardiovascular system--in antihypertensive and antianginal therapy is discussed. Hypertension and angina remain two of the most important risk factors for cardiovascular morbidity and mortality. Early-morning increases in blood pressure do not seem to be attenuated by many currently available sustained-release and extended-dosing formulations of anti-hypertensive agents, such as atenolol, enalapril, sustained-release verapamil, nitrendipine, nifedipine, diltiazem, and long-acting propranolol. A 24-hour controlled-onset, extended-release delivery system (COER-24) for verapamil hydrochloride has recently been developed to address the pharmacokinetic and circadian challenges to controlling blood pressure and angina. COER-24 for verapamil hydrochloride, the first chronopharmacologic agent approved for the treatment of both hypertension and angina, is designed for bedtime administration. It provides the highest concentration of drug in the blood during the early hours of the day, when blood pressure and heart rate are rising rapidly. COER-24 for verapamil hydrochloride has a more favorable adverse-effect profile than is seen with immediate-release verapamil. COER-24 for verapamil hydrochloride provides effective blood pressure reduction for 24 hours and protects against the early-morning increase in blood pressure; the drug has a more favorable adverse-effect profile than immediate-release verapamil.

Weakness of mucosal barrier in portal hypertensive gastropathy of alcoholic cirrhosis. Effects of propranolol and enprostil

Background/Aims: It has been suggested that the vulnerability of gastric mucosa is increased in patients with cirrhosis as a result of a PGE2 deficiency. Therefore, we evaluated whether PGE2 mucosal generation, and gastric potential difference - a reflection of the gastric mucosal barrier - were correlated to endoscopic features and whether these alterations could be alleviated. Methods: The potential difference was measured before (basal) and after a stimulation test by aspirin. The serum levels of gastrin and glucagon were also determined. Finally, the effects of a 1-week administration of propranolol or enprostil were tested on potential difference. The endoscopic grade of portal hypertensive gastropathy was assessed according to McCormack et al. The results are presented respectively for controls, patients with mild gastropathy, and patients with severe gastropathy. Comparisons were made using variance or covariance analysis after adjustment with age. Results: Basal potential difference was significantly different betweeen the three groups: −30.6, −28.8, t-24.9 mV, p<0.05, respectively. The effects of aspirin administration on potential difference parameters were significantly different between the three groups (irritability index: 35±25, 92±98, 114±74 mV 2 · min, p<0.05, respectively) when non-responders to aspirin were excluded. PGE2 mucosal generation was significantly increased in both the antrum (9.8, 19.5, 19.7 ng/mg proteins, p<0.05, respectively) and in the corpus (8.1, 14.0, 20.2 ng/mg proteins, p<0.05, respectively). PGE2 generation was not related to potential difference. Glucagon serum levels were related to the grade of gastropathy. A 1-week administration of 160 mg/d long-acting propranolol, 35 μg/d enprostil or placebo did not significantly modify basal potential difference. Conclusions: Portal hypertensive gastropathy is characterized by a decreased potential difference proportional to the endoscopic severity. The gastric mucosa of patients with cirrhosis seems to be more susceptible to aspirin than that of healthy subjects. It appears that the role of PGE2 is controversial in portal hypertensive gastropathy. Propranolol and enprostil do not improve this decreased potential difference.

Nifedipine gastrointestinal therapeutic system (GITS). A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in hypertension and angina pectoris.

Nifedipine 'gastrointestinal therapeutic system' (GITS) is a recently developed formulation that slowly releases the drug into the intestinal tract over a 24-hour period. When administered once daily, it is of similar efficacy to sustained release formulations of felodipine, verapamil, and diltiazem and at least as effective as standard formulations of lisinopril and enalapril, and long-acting propranolol and atenolol in the treatment of patients with mild to moderate essential hypertension. Substitution of nifedipine GITS for conventional formulations of nifedipine, diltiazem or verapamil, maintained adequate control of anginal symptoms in patients with stable angina pectoris. Nifedipine GITS appears to maintain quality of life and is apparently better tolerated than those formulations of nifedipine which require 2 or 3 times daily administration in both elderly and younger patients. In addition, it has minimal effect on lipid and glucose metabolism and reverses left ventricular hypertrophy, and is thus suitable for treatment of the majority of patients with mild to moderate hypertension or angina pectoris.

Practice and Economics Cost Considerations in Headache Treatment Part 1: Prophylactic Migraine Treatment

Effective migraine treatment is clearly the most cost-effective in terms of both direct and indirect costs. Patient education, behavior changes, and prudent medication selection can minimize costs. Low-dose aspirin may reduce headache frequency. Among the antidepressant medications used, amitriptyine 25 mg, 3 qhs ($4.16/month) and doxepin 25 mg, 3 qhs ($10.50/month) remain the standard. Imipramine (25 mg, 3 qhs ($3.75/month) is very inexpensive and should replace nortriptyline 25 mg, 3 qhs ($64.29/month) as a second-line agent. The specific serotonin reuptake inhibitors are expensive and have no proven effect for migraine prevention. Propranolol 80 mg bid ($7.80/month) is inexpensive and frequently a good choice among beta-blockers. Atenolol 100 mg qd ($27.50/month) is less expensive than long-acting propranolol 160 mg ($35.56/month) and nadolol 120 mg qd ($43.68/month) with equivalent effectiveness. It is thus recommended as the long-acting beta-blocker of choice. Sustained-release preparations of verapamil 240 mg qd ($31.98/month) are twice the cost and less well-absorbed than the standard preparation of 120 mg bid ($17.62/month). Better information is needed concerning effectiveness and optimal dosing of some older low-cost medications in the preventive treatment of migraine.

Effects of Long-Acting Propranolol on Agonistic and Stereotyped

Department of Psychology and George Jervis Clinic, New York State Institlute for Basic Research In Developemnt Disabilits, Staten Island, New York

Effect of propranolol (long-acting) on the circadian fluctuation of tissue-plasminogen activator and plasminogen activator inhibitor-1

The incidence of myocardial infarction and sudden cardiac death is highest in the morning. Inhibition of fibrinolytic activity in blood also peaks in the morning and this inhibition may favor the development of arterial thrombosis. It has been reported that patients treated with β blockers do not show the typical circadian pattern of onset of myocardial infarction and sudden cardiac death. This study was undertaken to investigate whether β blockade alters the circadian rhythm of 2 major fibrinolytic factors, tissue-plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). Repeated blood samples were taken over a 24-hour period in 13 healthy volunteers: 7 taking 160 mg/day of long-acting propranolol orally for 14 days, and the other 6 taking no medications. Blood samples were analyzed for the plasma levels of t-PA activity, t-PA antigen, PAI activity and PAI-1 antigen. A significant circadian variation of all 4 parameters was present in both groups. No significant differences in peak and nadir values, 24-hour mean, amplitude of fluctuation, and time of peak and nadir were found between the treated and untreated subjects. The data therefore suggest that propranolol treatment does not affect the plasma concentrations at rest or the endogenous circadian rhythm of t-PA and PAI-1 in healthy volunteers. The reported alteration in the circadian pattern of onset of myocardial infarction and sudden cardiac death by β blockers does not appear to be mediated by effects on the fibrinolytic system.

Role of Atrial Natriuretic Peptide in Hemoconcentration During Exercise

Changes in plasma levels of atrial natriuretic peptide (ANP) and albumin, and blood hematocrit (Hct) during treadmill exercise were studied in 6 healthy men before and after beta-adrenergic blockade. Plasma ANP levels increased during exercise and then gradually decreased. There was a concomitant increase in both Hct and plasma albumin concentrations. Prior administration of a long-acting propranolol, 160 mg daily for 3 consecutive days, markedly elevated plasma ANP levels before, during and after exercise. In addition, the mean basal Hct increased significantly and further rose during exercise after propranolol administration. When increments in plasma ANP concentrations during exercise in individual subjects were compared with those in Hct, there was a significant positive correlation between the two variables before and after propranolol administration. The results indicate a close relationship between the changes in plasma ANP and those in Hct during exercise at different ANP levels, and suggest that ANP may be at least one of the factors involved in the hemoconcentration associated with exercise.

Pulmonary effects of long-term β2-blockade in healthy subjects: Comparative study of metoprolol OROS

The effects on airway response of metoprolol OROS (oral osmotic) and three other long-acting β-adrenoceptor blockers were studied. This was a placebo-controlled, randomized, five-period, single-blind, crossover trial in 15 healthy volunteers. Bronchial β-blockade was estimated as the displacement of the salbutamol bronchodilator response of specific airway conductance (SGAW) measured by whole-body plethysmography. Metoprolol OROS ( 14 190 mg ), slow-release (SR) metoprolol (200 mg), atenolol (100 mg), long-acting (LA) propranolol (160 mg), and placebo were given once daily for 7 days. Inhaled salbutamol was administered at peak drug levels in cumulative doses of 12.5 to 800 μg on day 5 and in a single dose of 400 μg on day 7. On day 5, salbutamol induced significant increases in SGAW in each treatment group. SGAW increased after the single dose of salbutamol on day 7 in all groups and then declined steadily. The highest values were found after placebo and metoprolol OROS, with smaller increases after SR metoprolol, atenolol, and LA propranolol, the latter showing the smallest increase. Therefore, it would appear that under steady-state conditions, β 2-bronchial receptors are least blocked by metoprolol OROS, followed by SR metoptolol, atenolol, and LA propranolol.

Influences of propranolol and atenolol on the circadian rhythm of heart rate in elderly patients with essential hypertension

1. The influence of long-acting propranolol and of atenolol on the circadian rhythm of heart rate was assessed using 24 h electrocardiographic recordings in elderly patients with essential hypertension. Eighteen elderly patients were investigated before treatment and after 12 weeks on 60 mg of long-acting propranolol once a day; 21 elderly patients were studied before treatment and after 12 weeks on 50 mg of atenolol once a day. The mean hourly heart rate in 24 h electrocardiographic recordings was used to fit cosine curves by the statistical technique of least squares, and the following parameters were estimated: mesor (rhythm-adjusted mean of the heart rate), amplitude (one-half of the total diurnal variation of the heart rate) and acrophase (the time when the heart rate was at its peak above the mean). 2. The cosine curves were fitted with a P value of 0.01 or less before and after treatment in all patients. 3. In the long-acting propranolol group, the mesor and amplitude were reduced significantly after treatment. The acrophase appeared significantly earlier after treatment than before treatment. 4. In the atenolol group, the mesor and amplitude decreased significantly after treatment. However, the acrophase did not change with treatment. 5. We conclude that both propranolol and atenolol decrease the mesor and amplitude through blocking cardiac beta 1-receptors, and that only propranolol may have some effects on the central nervous system, resulting in the circadian phase shift.

Propranolol in the prevention of recurrent variceal hemorrhage in cirrhotic patients: A controlled trial

A double-blind controlled study of long-acting propranolol in the secondary prevention of variceal hemorrhage was conducted in 81 cirrhotic patients. After the index hemorrhage, all patients were treated with injection sclerotherapy on one occasion to secure hemostasis and then randomized within 72 h to propranolol or placebo therapy which was continued for 2 yr. Study endpoints were severe recurrence of variceal hemorrhage or death. Forty-two patients did not fulfill the entry criteria for the study. Thirty-eight patients received propranolol of whom 18 (47%) had further hemorrhage, 14 died, eight had side-effects (2 withdrawals), and 3 did not complete follow-up. Forty-three patients received placebo of whom 33 (77%) had further hemorrhage, 19 died, 5 had side-effects (2 withdrawals), and 5 failed to complete follow-up. The median time from onset of hemorrhage to starting drug therapy was 6 days for both groups. Life table analysis showed an equivalent incidence of further hemorrhage in both groups over the first 60 days, following which the propranolol group did consistently better than the placebo group. There was a significantly lower incidence of rebleeding in modified Child's C patients receiving propranolol (39%) than those on placebo (90%). No statistically significant effect on mortality was seen. In this study, propranolol reduced the incidence of late recurrence of variceal hemorrhage in patients with cirrhosis.

Acute and chronic effects of propranolol and primidone in essential tremor.

We studied the acute and chronic effects of propranolol and primidone in essential tremor by administering long-acting propranolol (80 to 160 mg/d) and primidone (50 to 250 mg/d) to 50 patients. We evaluated patients at 1, 3, 6, 9, and 12 months after treatment and assessed tremor by subjective rating by patients, clinical scoring, and thermographic (accelerometer) recordings. Acute adverse reactions occurred in 8% with propranolol and 32% with primidone. Propranolol was without therapeutic effect in 30%, and 32% had no benefit from primidone. Significant chronic side effects occurred in 17% taking propranolol and in 0% with primidone. Tolerance to drug effect occurred with chronic treatment in 12.5% of patients with propranolol and 13.0% with primidone. We conclude that propranolol and primidone are effective long-term treatment for some patients with essential tremor. Acute adverse reactions with primidone and side effects with chronic use of propranolol hamper therapy.

Pharmacodynamic and pharmacokinetic study of propranolol in patients with cirrhosis and portal hypertension.

1. The aim of this study was to investigate the pharmacokinetics and the beta-adrenoceptor blocking activity according to time of conventional (C) and long acting (LA) propranolol in cirrhotic patients. Twenty-four patients with alcoholic cirrhosis and oesophageal varices were randomly assigned to receive either 160 mg C propranolol, 160 mg LA propranolol or placebo acutely and then following repeated administration (acute and chronic phases). Thereafter propranolol concentrations and beta-adrenoceptor blockade (resting and exercise heart rates) were measured at different intervals. 2. The Cmax was significantly higher with C propranolol in both phases. The time of Cmax was significantly later with LA propranolol in both phases. The AUCs were significantly higher after chronic administration with both formulations of propranolol. 3. The exercise peaks of beta-adrenoceptor blockade were similar between the two formulations and between the two phases of administration of propranolol. The duration of effective beta-adrenoceptor blockade was significantly longer in the chronic phase and seemed to be longer with LA than with C propranolol although this was not significant (72 +/- 31 vs 48 +/- 18 h, respectively). 4. There was a significant correlation between the log propranolol concentration and exercise heart rate but not with resting heart rate. No correlation could be demonstrated between pharmacological data and the Child Pugh score. 5. We conclude that in cirrhotic patients exercise testing was a reliable method in the assessment of beta-adrenoceptor blockade. Pharmacology of propranolol was found to be different according to the formulation or to the phase of administration.

Effects of long-acting propranolol on A.M. and P.M. peaks in silent myocardial ischemia

The frequency of episodes of silent myocardial ischemia and the adverse impact of these episodes on cardiovascular morbidity and mortality have been demonstrated in several studies involving both symptomatic and asymptomatic subjects. Previous reports using a variety of agents—nitrates, 1 β blockers 2 and calcium antagonists 3—have shown the efficacy of these drugs in reducing ischemic activity, but have not resolved the issue of whether the circadian variation in ischemic events could be totally abolished. Beta blockers have been shown to be successful in blunting the a.m. peak, but there is little data concerning the P.M. peak. The present study was designed to test the hypothesis that β blockade with a long-acting propranolol preparation could abolish both a.m. and p.m. peaks in silent myocardial ischemic activity.

Effect of β-Adrenergic Blockade on Plasma Levels of Atrial Natriuretic Peptide During Exercise in Humans

Effect of beta-adrenergic blockade on plasma levels of atrial natriuretic peptide (ANP) during treadmill exercise was studied in 9 healthy volunteers. Plasma ANP levels increased during exercise. The mean plasma ANP concentration on 12-min exercise (32.5 +/- 3.7 pg/ml, mean +/- SEM) was significantly higher than the control (16.7 +/- 1.0 pg/ml). After exercise, the levels decreased and the mean plasma ANP concentrations in the recovery period were higher in subjects in the sitting position than in subjects who kept standing. Prior administration of a long-acting propranolol, 160 mg daily for 3 consecutive days, augmented ANP release during exercise. The mean plasma ANP concentrations on 9- and 12-min exercise (34.5 +/- 3.1 and 64.9 +/- 15.0 pg/ml, respectively) were significantly higher than those in the corresponding exercise stage without propranolol. Plasma ANP levels in the recovery period also increased after the administration of propranolol and the subjects in the sitting position again had higher plasma levels than those in the standing position. These results suggest that increased central blood volume during exercise elevates atrial pressure to stimulate ANP secretion, and that greater atrial distension and pressure due to reduced ventricular contractility by beta-adrenergic blockade facilitates ANP release to a greater extent.

Multicenter comparison of the nifedipine gastrointestinal therapeutic system and long-acting propranolol in patients with mild to moderate systemic hypertension receiving diuretics: A preliminary experience

The efficacy and safety of nifedipine in a gastrointestinal therapeutic system (GITS) push-pull osmotic pump formulation was compared with long-acting propranolol in 49 patients with mild to moderate hypertension already receiving diuretics. Using a two-week placebo run-in, double-blind study design, patients were randomly assigned to receive nifedipine GITS (n = 24) in doses of 30 mg, 60 mg, or 90 mg once daily; or long-acting propranolol (n = 25) in doses of 80, 160, or 240 mg once daily. Previous diuretic therapy was continued. Sitting and five-minute standing blood pressure and heart rate measurements were made 24 hours after dosing. At the endpoint of treatment, both nifedipine GITS and sustained-release propranolol reduced blood pressure compared with placebo (p <0.001) in the sitting and standing positions. Nifedipine GITS was more effective in lowering standing systolic blood pressure than was propranolol (p <0.02). Propranolol caused a greater reduction in resting heart rate than did nifedipine GITS (p <0.003). Both drugs were well tolerated. Nifedipine GITS is an effective and safe once-daily drug for use in patients with hypertension who are already receiving diuretics, may be more effective than sustained-release propranolol, and may be better tolerated than conventional nifedipine capsules.