Β-adrenergic Receptor Blocking Drugs Research Articles

Is a Mean Arterial Pressure Less Than 65 mm Hg an Appropriate Indicator of the Quality of Anesthesia Care?

Is a Mean Arterial Pressure Less Than 65 mm Hg an Appropriate Indicator of the Quality of Anesthesia Care?

β-Adrenergic Blockade in Cardiovascular Disease

The development and subsequent clinical application of the β-adrenergic receptor blocking drugs represent one of the major advances in human pharmacotherapeutics. No other class of synthetic drugs has demonstrated such widespread therapeutic utility for the treatment and prevention of so many cardiovascular diseases. In addition, these drugs have proven to be molecular probes that have contributed to our understanding of the disease, and on the molecular level, both the structure and function of the 7 transmembrane G protein receptors that mediate the actions of many different hormones, neurotransmitters, and drugs. The evolution of β-blocker drug development has led to refinements in their pharmacodynamic actions that include agents with relative β1-selectivity, partial agonist activity, concomitant α-adrenergic blockers activity, and direct vasodilator activity. In addition, long-acting and ultra-short-acting formulations of β-blockers have also demonstrated a remarkable record of clinical safety in patients of all ages.

Circulation Editors’ Picks

<i>Circulation</i> Editors’ Picks

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Pro: Beta-Blockers Are Indicated for Patients at Risk for Cardiac Complications Undergoing Noncardiac Surgery

Pro: Beta-Blockers Are Indicated for Patients at Risk for Cardiac Complications Undergoing Noncardiac Surgery

Synthesis of β-adrenergic blockers ( R)-(−)-nifenalol and ( S)-(+)-sotalol via a highly efficient resolution of a bromohydrin precursor

( R)- and ( S)-2-bromo-1-(4-nitrophenyl)ethanol are precursors of important β-adrenergic receptor blocking drugs ( R)-nifenalol and ( S)-sotalol, respectively. Both were obtained in enantiomeric pure forms via a single highly efficient enzymatic transesterification reaction of (±)-2-bromo-1-(4-nitrophenyl)ethanol using immobilized lipase PS-C-II ( E >1000; concn 200 g/L), while PS lipase completely failed to react. On the other hand, the hydrolytic method also produced enantiorich precursors though relatively less efficient (PS-C-II, E = 5.1). Out of all the approaches employed the transesterification method proved to be the most efficient.

The use of cardioselective β-blockers in a patient with idiopathic hypertrophic subaortic stenosis and chronic obstructive pulmonary disease

The β-adrenergic receptor blocking drugs are commonly used in the treatment of patients with idiopathic hypertropic subaortic stenosis (IHSS). These drugs, however, are contraindicated in patients with chronic obstructive pulmonary disease (COPD). We report the anesthetic management of a patient with IHSS complicated by severe COPD. We concluded that the β 1 selective, ultra-short acting β-blocker, esmolol, can be used intraoperatively when both conditions are present. The pathophysiology and the commonly used anesthetic drugs and practices for treatment of patients with IHSS are reviewed.

Selective β1-adrenergic receptor-blockade with atenolol enhances growth hormone releasing hormone and mediated growth hormone release in man

The growth hormone (GH) responses to a single bolus injection of the growth hormone releasing hormone (GRH) were examined in the basal state and in the presence of β-adrenergic receptor blocking agents of different specificity in ten normal men. During a constant five-hour infusion of 56 μg/min of propanolol (nonselective β-adrenergic receptor-blocker) in seven subjects studied, there was a significant augmentation of the GH release in response to exogenous GRH compared to the GH response during saline infusion, as measured by the peak serum GH concentrations after GRH ( P = 0.019) and the integrated GH values ( P = 0.019). A similar significant enhancement of GH responses to exogenous GRH as compared to the control day was observed with the specific β 1-adrenergic receptor-blocker atenolol in all seven subjects studied (four of whom also participated in the propanolol study). Both the peak GH response to a GRH bolus and the integrated GH values were significantly greater with atenolol ( P = 0.019 for both). There was no difference in serum GH concentrations after β-adrenergic receptor-blocking drugs during a three-hour sampling period before GRH administration compared to placebo. Our results support the concept that β-adrenergic receptors may modulate either the release or action of hypothalamic somatostatin in the control of GH secretion in man. We suggest the effect is mediated by specific β 1-adrenergic receptors.

Studies on LM protein appearing in submandibular glands of isoproterenol-treated rats. III. Some aspects of its formation.

A single stimulation with isoproterenol (IPR) resulted in a 1.5-fold increase in the total protein in saliva from rat submandibular glands at 1 day after the injection. Large mobile (LM) protein began to be secreted from the glands early after IPR injection, reaching a maximum at 2 days after injection, when the total protein in saliva had returned to the normal level. The secretion of this protein continued for 22 days after injection, indicating that the life of LM protein template is long or that the effect of IPR remains during this period. The increase of LM protein after IPR stimulation was markedly suppressed by β-adrenergic receptor blocking drugs. When both an α-adrenergic receptor blocking drug and adrenaline were injected together into rats, a small amount of the LM protein appeared and an increase in the wet weight of submandibular glands was seen. Repeated injection of these drugs resulted in a remarkable increase of LM protein. These results suggest that the appearance of LM protein was not a consequence of direct action of IPR but was due to a stimulatory effect of IPR on β-adrenergic receptors and that chronic blocking of α-adrenergic receptors has a significant stimulative effect on the production of LM protein through β-adrenergic receptors.

Effects of systemic and intracerebral administration of adrenergic receptor blocking drugs on the conditioned avoidance behavior and maze learning in rats

(1) Effects of α- and β-adrenergic receptor blocking drugs, given systemically or intracerebrally into the brainstem, were studied on the acquisition, retention and extinction of conditioned avoidance behavior. (2) The systemic administration of β-adrenergic receptor blockers, Trasicor and GYKI 41099, led to a marked suppression of the acquisition of a two-way avoidance response but did not modify the retention or the extinction of the avoidance response. (3) Injection of GYKI 41099 into the brainstem reticular formation resulted in a decrease in the acquisition of the conditioned avoidance response. (4) The same treatment with an α-adrenergic receptor blocker, phenoxybenzamine, failed to influence the acquisition of the conditioned avoidance response. (5) These observations led to the conclusion that β-adrenergic receptors are involved in modulating the acquisition of a conditioned response although they do not play a significant role in the retention or the extinction processes.

Pharmacodynamic properties of beta-adrenergic receptor blocking drugs in man.

β-Adrenergic receptor blocking drugs have been in clinical use for over 10 years, and have allowed pharmacological manipulation of one of the fundamental homeostatic mechanisms of the cardiovascular system. Their cardiac actions, namely a reduction in heart rate, a change in the pattern of left ventricular contraction and prolongation of atrioventricular conduction, are all explicable on the basis of inhibition of adrenergic receptors. Although ‘quinidine-like’ effects and partial agonist activity have been demonstrated pharmacologically, there is no evidence to suggest that they lead to any significant modification of the properties of β-adrenergic receptor blocking drugs given in therapeutic dosage.

Beta-adrenergic receptor blocking drugs in hyperthyroidism.

β-Adrenergic receptor blockade reduces many of the clinical manifestations of hyperthyroidism particularly tachycardia and dysrhythmias. β-Adrenergic receptor blocking drugs without intrinsic sympathomimetic activity are superior to those possessing it, probably because of the increased sensitivity to adrenergic receptor stimulation which is found in this condition. However, such treatment should not be considered as a long-term substitute for specific antithyroid therapy.

??-Adrenergic Receptor Blocking Drugs in Hypertension

The β-adrenergic receptor blocking drugs (β-blockers) are proving to be extremely useful in antihypertensive therapy. The reasons for their antihypertensive effect are not entirely clear, but a reduction in cardiac output and in renin release by the kidney seem to be the most probable explanations.

Adverse reactions to beta-adrenergic receptor blocking drugs: a report from the Boston collaborative drug surveillance program.

Of 14,344 hospitalised medical patients monitored in a drug surveillance program, 319 (2.4 %) received propranolol during one or more admissions. Angina and cardiac arrhythmias were the most common indications for therapy. Adverse reactions were attributed to propranolol in 30 (9.4 %) of the 319 patients. 22 of these reactions clearly involved impairment of cardiac function (bradycardia, heart block, hypotension, congestive heart failure), and in 8 cases they were considered life-threatening. Half of the adverse reactions occurred in patients taking low doses (less than 40 mg per day). In 11 cases, the reaction developed within 24 hours of the first dose. A literature survery of 797 ambulatory patients receiving oral propranolol revealed the most common adverse effects to be gastro-intestinal disturbances (11.2 % of patients), impaired cardiac function (6.9 %), and peripheral arterial insufficiency (5.8 %). Disturbances in central nervous system (CNS) function (fatigue, dizziness, impaired sleep, alterations in mood and thought) were also common. The data for propranolol suggest that treatment with β-adrenergic receptor blocking drugs is not without considerable risk, particularly in hospitalised patients with severe organic heart disease.

Beta-adrenergic receptor blocking drugs in angina pectoris.

Increased sympathetic activity involves increased oxygen consumption by the heart. β-Adrenergic receptor blocking (β-blocking) drugs generally reduce myocardial oxygen consumption. These drugs, regardless of their associated properties such as membrane stabilising action and intrinsic sympathomimetic effect, have all been found to increase exercise tolerance in angina pectoris. The membrane stabilising action has no relevance in the effect of these drugs in angina. The (+)-isomer of propranolol in clinical doses is devoid of haemodynamic action and is ineffective in angina, and the non-membrane-active β-adrenoceptor blocking drugs are effective antianginal agents. Acute exercise tests have failed to reveal any differences between the various β-blocking drugs, except Inpea which was found ineffective at maximum tolerated doses. However, short-term administration is different from long-term clinical use; certain side-effects are not apparent from single-dose administration. Therapeutic trials of β-blocking drugs have shown them to be effective prophylactics when administered over a long period. Trials that have not given clear results have been defective in design; inadequate ‘run-in’ period, sub-optimum fixed dosage and too short a period of assessment are common sources of error. Aspects of trial design are discussed as the response to β-blocking agents is assessed. Far the greatest experience has been with propranolol and best results have been obtained in trials that have used larger and individualised dosages. A clear dose response relationship has been established. Comparative trials of any two drugs in any condition requires that each should be given in optimum dosage if the assessment is to be meaningful. Studies with propranolol and practolol indicated that the former is more effective, and likewise, propranolol is superior to sotalol. Sotalol, which has minimum membrane stabilising activity, unlike practolol, was superior to a low dose (one eighth) of propranolol. Important contra-indications to β-blocking drugs are asthma (except the cardioselective practolol) and heart failure. If these contra-indications are observed β-blocking drugs are relatively safe. Dosage should be commenced at a low level and then gradually increased (say 25 % increments) until optimum effect is obtained. The greatest change in sympathetic environment of the heart occurs at the commencement of treatment (e.g. propranolol 10 mg 3 times daily) and it is then that heart failure may suddenly occur if patient selection has not been adequate. Subsequently, any small increase in dosage does not produce any sudden change in sympathetic environment and thus is relatively safe. An increase in dosage from say 500 mg three times daily of propranolol to 550 mg three times daily is negligible in pharmacological terms, and by such small percentage changes the dosage can be safely and gradually increased to the desired level.

??-Adrenergic Receptor Blocking Drugs in Cardiac Arrhythmias1

β-Adrenergic receptor blocking (β-blocking) drugs now have an established place in the elective and prophylactic treatment of many cardiac arrhythmias. In isolated preparations of heart muscle, these drugs inhibit spontaneous diastolic depolarisation and in high concentrations which are unlikely to have clinical relevance, they exhibit membrane-depressant properties. In intact animals and man they slow the rate of discharge of the sinus and ectopic cardiac pacemakers and increase the functional refractory period of the AV node. They also retard conduction, both anterograde as well as retrograde, in anomalous pathways of the heart.

Proceedings: Mode of action of beta-adrenergic receptor blocking drugs in hypertension.

Proceedings: Mode of action of beta-adrenergic receptor blocking drugs in hypertension.

Pharmacokinetic properties of the beta-adrenergic receptor blocking drugs.

The pharmacokinetic properties of the β-adrenergic receptor blocking drugs have been reviewed and discussed as a possible explanation for the wide range in therapeutic dose. As a general rule, the β-adrenergic receptor blocking action of these compounds is related, in a dose-dependent way, to their concentration in the circulation. The plasma concentrations of these drugs can vary widely after oral administration of the same dose in different individuals. This variation is especially great (up to 20-fold) for those drugs which have a high hepatic clearance (propranolol, alprenolol and oxprenolol), because a large and variable fraction of the drug is eliminated during the process of transfer of drug from the gut to the systemic circulation. Although half-life may be altered by route and duration of administration, it is always relatively short for propranolol, oxprenolol, alprenolol and pindolol (2 to 6 hours) necessitating a relatively short dosage interval. Practolol is unusual in that it is eliminated almost entirely by glomerular filtration and has a significantly longer half-life (9 to 12 hours). Although no data are available, it is likely to give less variable plasma concentrations.

Direct arterial pressure and the electrocardiogram in unrestricted patients with angina pectoris.

Direct arterial pressure and electrocardiogram have been recorded over a 24 hr period in 8 males with angina pectoris who were completely unrestricted throughout the study. Twenty-five separate episodes of angina occurred, precipitated by exertion, eating, smoking, and anxiety, in addition to 2 spontaneous attacks and 2 episodes of nocturnal angina. All but 2 angina episodes were accompanied by a rise in both arterial pressure and heart rate. In the cases of spontaneous and nocturnal angina these pressure and rate changes began 10-15 min before the pain. In exertional angina these changes were related to the degree of activity involved, while in other instances there was a brief surge of pressure and rate occurring at the time of onset of pain. In each patient pain tended to occur at approximately the same level of pressure-rate product. ST-segment changes in the electrocardiogram showed no consistent pattern, occurring before or after the onset of pain, while in some episodes there was no significant change. A limited number of observations were made on the effect of glyceryl trinitrate and β-adrenergic receptor blocking drugs.

Stimulation of 32Pi Incorporation into Phosphatidylinositol and Phosphatidylglycerol by Catecholamines and β-Adrenergic Receptor Blocking Agents in Rat Pineal Organ Cultures

Abstract The effect of norepinephrine, other catecholamines, phenylethylamines, and β-adrenergic receptor blocking drugs on the incorporation of 32Pi into phospholipids of intact rat pineal glands was studied in organ culture. Individual pineal phospholipids were assayed for radioactivity after separation by two-dimensional thin layer chromatography. Improved chromatographic separations were obtained (Getz, G. S., Jakovcic, S., Heywood, J., Frank, J., and Rabinowitz, M. (1970) Biochim. Biophys. Acta 218, 441–452), if thin layer plates were washed with acetone instead of ether after development in the first solvent system. Addition of l-norepinephrine (0.3 mm) significantly stimulated the incorporation of isotope into phosphatidylinositol within 5 min and into phosphatidylglycerol after 15 min. After 3 hours' incubation, l-norepinephrine and other phenylethylamine derivatives, including d-norepinephrine, epinephrine, dopamine, tyramine, and octopamine stimulated incorporation into phosphatidylglycerol (100 to 500%) and phosphatidylinositol (100 to 200%). Incorporated radioactivity continued to increase for up to 16 hours, but norepinephrine-induced stimulation steadily declined. The stimulating effects of l-norepinephrine were essentially linear from 0.3 mm to 3 µm. No stimulation was observed in the presence of N6, O2'-dibutyryl adenosine 3',5'-monophosphate at a concentration as high as 10 mm. Several substances with widely differing potencies as β-adrenergic receptor blocking agents, including dl,-propranolol, d-propranolol, dichloroisoproterenol, and alprenolol, but not sotalol, increased 32Pi incorporation into pineal acidic phospholipids. However these agents gave a labeling pattern different from that produced by norepinephrine: labeling of phosphatidylglycerol was elevated 1000 to 1500%, of phosphatidylinositol up to 100%, and of phosphatidic acid, 50 to 150%. Neither sotalol nor propranolol prevented the stimulation of phospholipid metabolism caused by norepinephrine. These findings indicate that the increase in phospholipid radioactivity is not related to the formation of melatonin which in the cultured pineal is stimulated by either norepinephrine or N6, O2'-dibutyryl adenosine 3',5'-monophosphate. This conclusion is also supported by the fact that propranolol fails to block enhanced phospholipid labeling whereas it blocks enhanced melatonin formation. The data further indicate that the stimulation of phospholipid metabolism caused by drugs with β-adrenergic receptor blocking activity is not brought about through interaction with β-adrenergic receptors.