Β-adrenergic Blocking Drugs Research Articles

Hemodynamic effects and safety of sotalol in the prevention of supraventricular arrhythmias after coronary artery bypass surgery

Sotalol is a β-adrenergic blocking drug with the additional property of lengthening the cardiac action potential. These electrophysiologic properties render the drug attractive for use in the prevention of postoperative supraventricular arrhythmias (SVA), and previous studies have suggested that it was indeed effective. The hemodynamic response to sotalol and its safety early after coronary artery bypass graft (CABG) surgery were therefore studied. Forty-two patients undergoing CABG were randomly assigned either to receive sotalol to prevent postoperative SVA (25 patients) or to serve as controls (17 patients). Sotalol was started 6 hours after surgery if patients had a cardiac index >2.8 L/min/m 2 with a pulmonary capillary wedge pressure <15 mmHg, and if they had no contraindications to the use of β-blockers. The drug was given as a loading infusion of 1 mg/kg over 2 hours, followed by a maintenance infusion of 0.15 mg/kg/h for 24 hours. Three hours later, patients received the first oral dose of 80 mg to be repeated every 8 or 12 hours. Adverse effects necessitating discontinuation of the drug (bradycardia <50 beats/min, systolic blood pressure <90 mmHg, or cardiac index <2.2 L/min/m 2) occurred in six patients (24%) and were mainly related to the loading infusion. The hemodynamic data for patients who completed the study were characterized by a significant fall of the cardiac index caused by a lower heart rate without significant change of the stroke volume index. The incidence of supraventricular arrhythmias was not significantly different in the two groups ( 3 19 in the sotalol group, 5 17 in the control group). In conclusion, at the dosage used, sotalol was associated with a high incidence of adverse reactions, precluding the enrollment of enough patients to assess a possible efficacy in the prevention of postoperative SVA. Bradycardia, accompanied by a significant decrease of cardiac index, was found. Therefore, it is concluded that this drug should be used very cautiously after coronary artery surgery.

Retention prediction for β-adrenergic blocking drugs in normal-phase liquid chromatography

The slope-intercept and the convergence model were used for describing the normal-phase retention data for a set of β-adrenergic blocking drugs obtained on a cyanopropyl column using various proportions of hexane-2-propanol-0.1% propylamine as mobile phase. Moreover, a quantitative structure-retention relationship with log P as descriptor was derived. The normal-phase retention data were also found to be rather strongly correlated with the data obtained for the same β-adrenergic blocking drugs in reversed phase. This allowed to derive an equation for the prediction of normal-phase retention data from reversed-phase data and vice versa.

The Effects of ??-Adrenoreceptor Blockade on Oxygen Consumption During Cardiopulmonary Bypass

The effect of chronic beta-adrenoreceptor blockade (beta-blockade) on hemodynamics and oxygen consumption (VO2) during cardiopulmonary bypass (CPB) in mild hypothermia (34 degrees C) was studied in 34 patients. The study group included 17 patients who received beta-adrenergic blocking drugs for at least 1 mo prior to the study. Seventeen patients who did not receive beta-adrenergic blockers served as controls. Demographic data in the two groups were comparable. Prior to induction of anesthesia, the heart rate was slower in the beta-adrenergic blocker group as compared to the control group. During CPB, measurements were made at two pump flow rates: 2.4 L.min-1.m-2 and 3.0 L.min-1.m-2. Oxygen delivery was similar in the two groups (beta-adrenergic blocker vs control) but the oxygen consumption was significantly lower in the beta-adrenergic blocker group as compared to the control group at both flow rates (P = 0.009). Increasing the flow rate from 2.4 L.min-1.m-2 to 3.0 L.min-1.m-2 produced a similar increase (P = 0.0001) in oxygen consumption in both groups. Increasing flow rate increased mean arterial pressure (MAP) and central venous pressure (CVP) and decreased systemic vascular resistance index (SVRI) and reservoir volume similarly in both groups. Thus, compared to the control group, patients on chronic beta-adrenergic blocker medication have a lower VO2 during CPB.

β-Adrenergic blocking drugs and psoriasis

β-Adrenergic blocking drugs and psoriasis

Food intake of lean and obese Zucker rats following ventricular infusions of adrenergic agonists

The effect on food intake of adrenergic agonists administered into the third cerebral ventricle was studied in Zucker fatty and lean rats. The α 2 agonist, clonidine, produced a larger dose-related increase in food intake in lean rats than in the fatty rats. Dose-response curves show similar sensitivity, but decreased responsiveness in the lean animal. The β 2 adrenergic agonist, salbutamol, produced similar food effect in obese and lean rats reducing food intake in the lean rats at the highest dose (300 nmol), and in the fatty rats at the two highest doses. The effects were small in both groups. The β 2 agonist, BRL 37344, ((4-(2-((2-hydroxy-2-(3-chlorophenyl)ethyl)amino)-propyl)-phenoxy acetate)) produced a larger dose-related decrease in food intake in the fatty rat than in the lean rats. Dose-response curves showed that sensitivity of β-receptors was similar, but the lean animals were less responsive. The β-adrenergic blocking drug propranolol blocked the unorectic effect of BRL 37344 in the fatty rat. These studies suggest that in the fatty rat, the α 2 receptor system is tonically more active and the β 3 receptor system tonically less active, a relationship that would explain the hyperphagia and development of obesity in these animals.

Cardiovascular responses to hypoxia in the hagfish, Eptatretus cirrhatus

Simultaneous measurements of cardiac output (Q̇), blood pressures and blood gases were made in the hagfish, Eptatretus cirrhatus, during exposure to hypoxia. The partial pressure of oxygen in the medium (P i O 2 ) was reduced from 20.7 kPa to 8.0 kPa and then lowered to 5.3 kPa. At a P i O 2 of 5.3 kPa there was a 40% increase in Q̇. Part of the increase may have been due to the increased activity of the animal at low P i O 2 . In recovery, when the animals were inactive, Q̇ continued to rise to 160% of the control values. At 5.3 kPa, oxygen consumption (as determined by the Fick principle) fell to 29% of the normoxic value and was associated with increased branchial vascular resistance (Rg) and an increased diffusion limitation of the gills (L diff). Adrenaline increased heart rate and aortic blood pressures.Increased Rg and L diff could be provoked in normoxia by the injection of the β-adrenergic blocking drug propanolol. We suggest that catecholamines may be involved in the tonic control of gill vasomotor tone.

Centrally induced hypotensive effect of β-adrenergic blocking drugs

Centrally induced hypotensive effect of β-adrenergic blocking drugs

Direct separation of nadolol enantiomers on a Pirkle-type chiral stationary phase

The enantiomers of the β-adrenergic blocking drug nadolol may be separated on a chiral stationary phase following conversion to their 1-naphthylurea derivatives by reaction with the achiral reagent 1-naphthylisocyanate. A mixture of n-hexane, propan-2-ol and acetonitrile is used to elute the enantiomers from a column comprising ( R)-N-(3,5-dinitrobenzoyl)- l-leucine covalently bound to 5-μm aminopropylsilica. Nadolol is a cis-diol structure which has three stereogenic centres, however the two diol carbons are held in a fixed configuration and it therefore has only four optical isomers. These are resolved in under 30 mn using the procedure described herein, which is therefore suitable for use in the quality control context.

Hemodynamic responses to pancuronium and vecuronium during high-dose fentanyl anesthesia for coronary artery bypass grafting

The hemodynamic and electrocardiographic (ECG) effects of pancuronium and vecuronium were compared during high-dose fentanyl anesthesia for coronary artery bypass grafting (CABG) surgery. Forty-eight morphine-scopolamine premedicated patients scheduled for elective CABG were anesthetized with fentanyl (100 μ/kg) in divided doses, and either of two muscle relaxants, pancuronium (n = 26; 0.10 mg/kg) or vecuronium (n = 22; 0.09 mg/kg). Hemodynamic data, blood gas samples, and ECG tracings were obtained at the following intervals: (1) control; (2) prior to intubation; (3) 1 minute after intubation; (4) prior to sternotomy; and (5) 1 minute after sternotomy. In the pancuronium group, heart rate (HR), cardiac index (CI), and rate-pressure product (RPP) were increased after induction of anesthesia and following intubation. Eleven patients (42.3%) displayed ischemic ST segment changes. Four patients in this group developed tachycardia and hypertension to an extent requiring pharmacological intervention. Vecuronium-treated patients displayed no increases in HR, MAP, and RPP, and a decrease in CI. Only one patient (5.6%) developed evidence of ischemic ECG changes. Four patients in the vecuronium group, all receiving preoperative β-blocker therapy, became hypotensive and bradycardic after the induction of anesthesia. The present investigation confirms the increased incidence of myocardial ischemia during high-dose fentanyl-pancuronium anesthesia. Although vecuronium was associated with fewer myocardial ischemic changes, the occurrence of bradycardia and hypotension in some patients receiving preoperative β-adrenergic blocking drugs remains a concern.

Pharmacological evidence for involvement of the sympathetic nervous system in the increase in renin secretion produced by a low sodium diet in rats

To determine the degree to which increased sympathetic activity contributes to the increase in renin secretion produced by a low sodium diet, the β-adrenergic blocking drug propranolol or saline vehicle was injected through indwelling jugular cannulas in rats fed a normal diet and rats fed a low sodium diet for 9 days. Plasma renin activity (PRA) and plasma renin concentration (PRC) were elevated by the low sodium diet, and these values were reduced 42–45% by propranolol, although they were still higher than in the normal diet controls. Plasma corticosterone was moderately elevated in cannulated rats on regular diet, compared to decapitated controls, but corticosterone did not differ between cannulated and decapitated rats on low salt diet; propranolol reduced plasma corticosterone. However, PRA and PRC were comparable in cannulated rats and decapitated controls on both the normal and the low sodium diets, and propranolol did not produce a significant reduction in PRA and PRC in rats fed the normal diet. This indicates that the effects of propranolol on PRA and PRC in the low sodium rats were not simply due to reduction of a stress-induced increase in renin secretion. The results indicate that increased sympathetic activity makes a substantial contribution to the increase in renin secretion produced by 9 days of dietary sodium restriction.

β-Adrenergic Blocking Drugs in the Treatment of Congestive Heart Failure

Experimental and clinical data suggests that increased serum catecholamines may have predominantly detrimental effects in patients with congestive heart failure. Some investigators have proposed use of beta-blockers in heart failure as a means of ameliorating the harmful effects of the excess catecholamines. The clinical experience to date with use of these agents as therapy in congestive heart failure is limited but does suggest a future role for beta-blockers as adjunct therapy in a select population of patients with heart failure.

Pharmacological evidence that the sympathetic nervous system mediates the increase in renin secretion prodsuced by immobilization and head-up tilt in rats

To determine the mechanism by which immobilization and head-up tilt under inactin anesthesia increase plasma renin activity (PRA), the effect of these stimuli on plasma levels of vasoactive intestinal polypeptide (VIP) were measured and the effect of the β-adrenergic blocking drug, propanolol on the response of plasma renin activity determined. Increases in circulating VIP are known to stimulate secretion of renin. After 10 min of immobilization, plasma renin activity was increased and VIP in plasma was unchanged. After 30 min of tilting, plasma renin activity was also increased and VIP in plasma was unchanged. The increases in plasma renin activity were blocked by propranolol. Inactin anesthesia by itself increased plasma renin activity and this response was unaffected by propranolol and associated with a small decrease, rather than an increase in VIP in plasma. The results indicate that the responses of plasma renin activity to immobilization and head-up tilt are due to increased secretion of renin mediated by the sympathetic nervous system. On the other hand, the increase in secretion of renin produced by inactin anesthesia does not appear to be mediated by the sympathetic nervous system. There was no evidence that VIP was responsible for any of the increases.

Medical Prophylaxis for the Post Myocardial Infarct Patient

The use of beta-adrenergic blocking drugs has been shown to benefit many post myocardial infarction patients. Aspirin is useful for secondary prevention and a subset of patients may benefit from short term anticoagulation.

Age and antihypertensive drugs (hydrochlorothiazide, bendroflumethiazide, nadolol and captopril)

Three double-blind Veterans Administration Cooperative Studies are reviewed to determine age-related changes in response to antihypertensive agents. In the first study 312 patients received hydrochlorothiazide titrated from 25 to 100 mg twice daily to lower diastolic blood pressure (BP) to <90 mm Hg. Of 121 patients aged 55 to 65 the decrease in BP averaged −21.8 −12.9 mm Hg, while in the 191 patients younger than 55 the reduction averaged −15.7 −11.5 mm Hg (p < 0.001; p = 0.048, respectively). Both systolic and diastolic BP reductions averaged significantly more in older whites; in older blacks it was systolic BP only. An additional 298 patients received titrated doses of propranolol alone, in this group there were no significant differences in BP response between younger patients and patients aged 55 to 65 except in the subgroup of white patients older than 60, in whom the systolic reduction was significantly less than in the younger patients. In a second study of bendroflumethiazide alone and with nadotol, systolic BP decreased more in older than in younger patients but there was no agerelated reduction with nadotol atone. In the third trial captopril was first given atone and later with hydrochlorothiazide. There were no age-related differences with captopril alone, but after the addition of hydrochlorothiazide there was a trend toward a greater antihypertensive response in the patients aged 55 to 69. Thus, responsiveness of older patients varies with the type of antihypertensive drug. Age appears to increase the antihypertensive response to thlazide diuretics but not to β-adrenergic blocking drugs or to captopril.

Antiarrhythmic effects of beta-adrenergic blocking agents in benign or potentially lethal ventricular arrhythmias

Classification of ventricualr arrhythmias into those that are benign, potentially lethal and lethal is based on their associated risk for producing sudden cardiac death. This classification system is useful in defining indications for the treatment of ventricular arrhythmias and predicting differential rates of antiarrhythmic drug efficacy and toxicity. Whether the reduction of potentially lethal ventricular arrhythmias will prevent sudden cardiac death remains to be determined. The class II antiarrhythmic agents—the β-adrenergic blocking drugs—have been shown to reduce sudden cardiac death in postmyocardial infarction patients, but the precise mechanism of their effect has not been defined, β blockers are efficaclous in approximately 50% of patients with benign or potentially lethal ventricular arrhythmias. This response is comparable to that seen with the class IA agent disopyramide or the class IB agents tocainide and mexiletine. β blockers have favorable side-effect profiles including a low incidence of proarrhythmia and a lack of organ toxicity such as hepatitis, pulmonary fibrosis or agranulocytosis, which are concerns with class I and class III antiarrhythmic drugs. The proper dosage of the β blocker is critical in limiting adverse effects. In a study of 23 patients with benign or potentially lethal ventricular arrhythmias, 11 (48%) of the patients responded to nadolol with a reduction of >75% in arrhythmia frequency, and several patients responded at nadolol dosages as low as 10 mg daily. Thus, it is plausible to consider β blockers as first-choice antiarrhythmic therapy, even in patients with left ventricular dysfunction when sympathetic tone is not required to maintain cardiac compensation.

Electrophysiologic effects of beta blockers in ventricular arrhythmias

β-adrenergic receptor blocking agents are effective antiarrhythmic drugs in patients with ventricular arrhythmias. However, these agents exert little or no measurable electrophysiologic effect on normal Purkinje and ventricular muscle fibers when administered acutely. They prevent catecholamine-induced increases in Purkinje fiber automaticity and may interfere with catecholamine-dependent slow responses. β-adrenergic blocking drugs also prevent the decrease in ventricular fibrillation threshold induced by catecholamines. In the acutely ischemic ventricle, some β blockers selectively depress conduction within the ischemic zone. The long-term administration of some β blockers has, in contrast to their short-term effects, been shown to prolong action potential duration and effective refractory period in the ventricle. Which of these observed electrophysiologic effects, either alone or in combination, contributes to the ventricular antiarrhythmic effects of β-blocking drugs in man is at present unknown.

Beta-blocker therapy for the Wolff-Parkinson-White syndrome

Two types of arrhythmias are associated with the Wolff-Parkinson-White syndrome: those in which the accessory pathway is a required part of the reentrant circuit, e.g., orthodromic atrioventricular reciprocating tachycardia, and those that conduct over the accessory pathway but do not require its activation for maintenance of tachycardia, e.g., atrial flutter/fibrillation. Increased sympathetic tone shortens the refractoriness of atrial and ventricular tissue; however, conduction in the atrium and ventricle is not considered the limiting factor for maintenance of atrioventricular reciprocating tachycardia or conduction over the accessory pathway in atrial arrhythmias. Intravenous β-adrenergic blockers given to patients in the resting state have a minimal to moderate effect in depressing atrioventricular nodal conduction, but have little or no effect on accessory pathway refractoriness or conduction in most patients. In patients presenting with atrioventricular reentry, intravenous administration of β-adrenergic blocking drugs often is not effective to terminate tachycardia. However, long-term oral therapy with these agents may be beneficial, especially in patients in whom enhanced sympathetic tone is responsible for the initiation or maintenance of tachycardia.

Effects of Metoprolol, Alone and in Combination with Lidocaine, on Ventricular Fibrillation Threshold

Metoprolol and other beta-adrenergic blocking drugs are known to exert cardioprotective effects that include significant reduction in occurrence of ventricular fibrillation (VF) following myocardial ischemia and infarction. To help determine the mechanism of these cardioprotective effects, this study evaluated the effect of equipotent beta-blocking doses of metoprolol and three other beta-blockers with differing ancillary properties on ventricular fibrillation threshold (VFT) in the normal canine heart. Metoprolol tartrate (1.0 mg/kg i.v.), atenolol (0.3 mg/kg i.v.), propranolol hydrochloride (0.3 mg/kg i.v.), pindolol (0.03 mg/kg i.v.), or saline control (0.9% NaCl solution; vehicle) was given, alone and in combination with lidocaine (L), to groups of six pentobarbital (32.5 mg/kg i.v.) anesthetized mongrel dogs after control VFT and control isoproterenol-induced (ISO) positive chronotropic effects had been determined. The D- (membrane stabilizing, non-beta blocking) and L- (beta blocking) isomers of propranolol also were administered to separate groups of six anesthetized dogs in a dose of 0.3 mg/kg i.v. Blood samples (venous) were taken before drug or vehicle administration, 10 min after drug/vehicle administration and at half-hour intervals thereafter during experimentation. ISO responses and VFT were determined 5 and 15 min, respectively, after drug/vehicle administration and at half-hour intervals for a total experimental period of 165 min. VF was induced with a train of pulses (5 s, 100 Hz, 3-ms duration, 250-omega resistance) applied by bipolar platinum electrodes to a paced heart (200 beats/min). Voltage (V) was increased every 60 sec (0.25-V increments between 0-3.5 V and 0.5-V increments greater than 3.5 V) until VF occurred. Metoprolol increased VFT significantly (p less than 0.05) and maximally (max delta V = 2.3 +/- 0.7 V) at 135 min postdrug when the ISO-induced increase in heart rate was inhibited (%I ISO) by less than 53%. Max delta V was not significantly increased following i.v. administration of atenolol (0.8 +/- 0.6 V), pindolol (0.1 +/- 0.1 V), or saline (0.1 +/- 0.1 V). Max delta V was 0.5 +/- 0.2 in the D-propranolol-treated group and 0.5 +/- 0.3 in the L-propranolol-treated group. These values did not differ from max delta V obtained in the propranolol-treated group (0.6 +/- 0.4 V). Changes in VFT for all groups were, over time, negatively correlated with %I ISO and were not dependent on membrane stabilizing effect (metoprolol, propranolol (D,DL), pindolol), intrinsic sympathomimetic activity (pindolol), or cardioselectivity (metoprolol, atenolol).(ABSTRACT TRUNCATED AT 400 WORDS)

Changes in ventricular septal thickness in systemic hypertension during treatment with methyldopa and prazosin

Centrally active antihypertensive drugs such as methyldopa, β-adrenergic blocking drugs, labetalol and angiotensin converting enzyme inhibitors reduce left ventricular (LV) mass, although this property is lacking in drugs acting only on the peripheral α receptors (hydralazine and minoxidil). 1 The effect of prazosin, a peripheral vasodilator and a frequently used antihypertensive drug, has previously not been studied. In a single-blind crossover study, we looked at the effect of this drug on ventricular septal (VS) thickness and posterior LV wall thickness, comparing it with the effect of methyldopa, using echocardiography.

Calcium Channel blockers: Spectrum of Side Effects and Drug Interactions

Calcium antagonists are a chemically heterogenous group of agents with potent cardiovascular effects which are beneficial in the treatment of angina pectoris, arterial hypertension and cardiac arrhythmias. The main side effects for the group are dose-dependent and the result of the main action or actions of the calcium antagonists, i.e. vasodilatation, negative inotropic effects and antiarrhythmic effects. Pronounced hypotension is reported for the main calcium antagonist drugs; verapamil, diltiazem and nifedipine. While conduction disturbances and bradycardia are seen more often after verapamil and diltiazem, tachycardia, headache and flush are more frequent after nifedipine. Constipation is relatively frequent after verapamil while nifedipine is reported to induce diarrhea in som patients. Idiosyncratic side effects are rare but have been reported from the skin, mouth, musculoskeletal system, the liver and the central nervous system. These side effects include urticarial rashes, gingival hyperplasia, arthralgia, hepathotoxicity and transistory mental confusion or akathisia. Verapamil, diltiazem and possibly also nifedipine have been reported to increase serum digoxin concentrations but the clinical relevance of these drug interactions are not clear. Furthermore, verapamil and diltiazem may potentiate the effects of beta-adrenergic blocking drugs and verapamil may also potentiate the effects of neuromuscular blocking drugs. It is concluded that side effects after calcium antagonist drugs are mostly trivial and transient although they may sometimes be relatively common. Clinically relevant drug interactions are few. Judged from the point of efficacy and safety, calcium antagonists will have a major place in the future pharmacotherapy of several cardiovascular disorders.