Intravenous Pindolol Research Articles

Hemodynamic effects of pindolol and atenolol at rest and during isometric exercise: A noninvasive study with healthy volunteers

Hemodynamic effects of intravenous and oral pindolol and atenolol were assessed in ten healthy volunteers by left ventricular echocardiography and systolic time intervals. Measurements were made at rest and during hand-grip-induced isometric exercise. Drug doses were pindolol 0.015 mg/kg intravenously and 10 mg/day orally, atenolol 0.1 mg/kg intravenously, and 50 mg/day orally. Heart rate at rest was reduced by both drugs. The reduction caused by atenolol during oral treatment was significantly greater (p less than 0.01). Intravenously only pindolol reduced mean arterial pressure. During oral treatment atenolol reduced the mean arterial pressure nonsignificantly. Both drugs lowered heart rate during isometric exercise, atenolol being significantly more effective. During oral treatment atenolol blunted the heart-rate reaction to exercise. Mean arterial pressure during isometric exercise rose slightly with both drugs after intravenous administration. During oral treatment only atenolol reduced the mean arterial pressure significantly. Intravenous atenolol reduced cardiac contractility at rest, indicated by significant decreases in fractional shortening, ejection fraction, and the mean velocity of circumferential fiber shortening. In contrast, intravenous pindolol and oral therapy with either drug did not change contractility. Intravenous atenolol raised total peripheral resistance. The preejection period/left ventricular ejection time ratio decreased with intravenous pindolol, while atenolol increased it. In conclusion, atenolol had more negative inotropic and chronotropic effects, especially after acute intravenous administration. Only atenolol reduced cardiac output and increased peripheral resistance. After repeated oral administration, these effects were less apparent.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Pindolol on Neurosympathetic Responsiveness, Blood Flow Variability, and Conduction in Acutely Ischaemic Myocardium

The effects of a beta-adrenoceptor antagonist with partial agonist activity (pindolol) were assessed in the open-chest anaesthetised dog during 12-minute periods of left anterior descending coronary artery (LAD) occlusion and reperfusion before and after sympathetic stimulation. Regional myocardial catecholamine efflux, blood flow, and epicardial activation abnormalities were assessed in three groups. In a control group (n = 8), two periods of ischaemia resulted in reproducible intraexperimental changes in catecholamine responses, blood flow, conduction abnormalities, and arrhythmias. Intravenous (i.v.) pindolol (0.45 mg/kg before the second occlusion) reduced nerve-stimulated norepinephrine (NE) overflow from nonischaemic (NI) myocardium but did not modify overflow from ischaemic (I) myocardium either during ischaemia or reperfusion. At constant heart rate (atrial pacing, n = 8), pindolol reduced absolute blood flow to I and NI but had no effect on the ratio of endocardial/epicardial blood flow, arrhythmias, or activation abnormalities during occlusion. Following a reduction in heart rate of 32 +/- 6 beats/min (no pacing, n = 8), pindolol resulted in similar reduction in blood flow to I and NI but also increased the ratio of endocardial/epicardial flow and reduced both spontaneous arrhythmias and activation delay during occlusion. The acute effects of pindolol on conduction abnormalities, arrhythmias, and blood flow distribution in I are thus dependent on reduction in heart rate.

Failure of intravenous pindolol to reduce the hemodynamic determinants of myocardial oxygen demand or enzymatically determined infarct size in acute myocardial infarction: Owensby DA, O'Rourke ME Aust NZ J Med 1985; 15:704–711

Failure of intravenous pindolol to reduce the hemodynamic determinants of myocardial oxygen demand or enzymatically determined infarct size in acute myocardial infarction: Owensby DA, O'Rourke ME Aust NZ J Med 1985; 15:704–711

The effect of pindolol on exercise-induced increase in plasma vasoactive prostanoids and catecholamines in healthy men

The effect of intravenous pindolol (0.0256 mg/kg) on changes in plasma arachidonic acid (AA), some of its metabolites, and catecholamines induced by submaximal exercise was studied in six healthy male volunteers. Exercise resulted in markedly increased plasma concentrations of thromboxane B 2 (TxB 2) from 0.13±0.01 to 0.27±0.02 pmol/ml (mean±SEM; p<0.05) and AA from 4.1±0.6 to 8.0±0.9 μmol/1 (p<0.005). No significant changes were seen in plasma concentrations of 6-keto-PGF 1α or PGE 2 during exercise. A marked increase in plasma noradrenaline was seen already at 15 min of exercise, while the adrenaline concentration increased significantly at 30 min of exercise and a very marked increase in the adrenaline concentration was seen at exhaustion. A positive correlation (r=0.54; p<0.05) was seen between plasma TxB 2 and plasma adrenaline during exercise. The peak increase in both of these parameters was seen simultaneously at exhaustion. Pindolol treatment resulted in almost total inhibition of the increase in plasma TxB 2 and AA during exercise. Pindolol treatment also resulted in a significantly higher adrenaline level at exhaustion. These data seem to indicate that an increased sympathetic tone may result in an increased release of arachidonic acid and the formation of vasoconstrictive thromboxane A 2.

The sympathomimetic activity of (±)-pindolol at β 1- and β 2-adrenoceptor sites

In isolated right atrial and stilboestrol-pretreated uterine preparations from both guinea-pigs and rats, pindolol elicited propranolol-sensitive positive chronotropic and smooth muscle relaxant actions. Although the pD 2 values for pindolol (8.4–9.2) and (−)-isoprenaline (ISO, 8.4–8.7) fell within the same range in these preparations, the maximum responses to pindolol were less than 15% of those to the catecholamine. Thus, pindolol did not display any selectivity for agonistic actions at β 1- or β 2-adrenoceptors. In uteri taken from progesterone-pretreated rats, the pD 2 value for (−)-isoprenaline was 9.5 and that of pindolol 8.5. In these preparations the maximal relaxant effect of pindolol (approximately 50% E max ISO) was greater than that found in oestrogen-pretreated uteri. Thus, it appears that the maximal response of pindolol in vitro can be related to the pD 2 value for (−)-isoprenaline. In anaesthetized cats, intravenous pindolol elicited non-β-adrenoceptor-mediated increases in heart rate and decreases in soleus muscle contractility. The mechanism(s) underlying the latter actions are unknown.

Effects of pindolol on renal function II. Effects of intravenous and prolonged oral dosing

Effects of intravenous and long-term oral dosing with pindolol on renal function were examined in eight hypertensive patients with reduced renal function. (Inulin clearance ranged from 40.5 to 84.5 ml/min/1.73 m2.) Intravenous pindolol resulted in decreased mean heart rate (74.3 to 67 bpm) and decreased mean inulin clearance (66 to 60.5 ml/min/1.73 m2.) Blood pressure and renal plasma flow did not change significantly. Long-term oral pindolol depressed blood pressure and heart rate, but mean inulin clearance was unchanged and renal blood flow and plasma volume increased. A second intravenous pindolol dose, given while the patients were receiving oral doses, resulted in nonsignificant decreases in glomerular filtration rate and renal plasma flow, but no change in blood pressure and heart rate. We conclude that prolonged pindolol dosing in patients with reduced renal function had no effect on renal function. When the drug was given intravenously there were small decreases in glomerular filtration rate and renal plasma flow.

Observations on three dosage forms of pindolol

Cardiac effects of single doses of conventional oral pindolol, sustained-released oral pindolol, and intravenous pindolol were studied in healthy male volunteers, aged 21 to 27 years, weighing 70.8 to 92.1 kg. The studies were designed to evaluate the oral dose-response curve of pindolol, to assess the partial agonist activity of pindolol, to determine the systemic bioavailability of oral pindolol, and to compare the systemic bioavailability, potency, and duration of action of comparable beta-adrenergic-blocking doses of pindolol and propranolol. In study A, eight subjects randomly received at weekly intervals oral pindolol, 5, 10, 15, and 20 mg (2 × 10 mg), and sustained-release pindolol, 20 and 30 mg. Supine resting (RHR), standing (SHR), and exercise heart rates (EHR) were recorded at 0 hours (before dose) and at 2, 8, and 24 hours after dose. Control RHR averaged 57.0, SHR 98.2, and EHR 162.8 bpm. None of the doses produced any significant reduction in RHR or SHR. Average EHR at 2 hours was 122.3 bpm, with no significant difference between the six doses. At 8 and 24 hours, the larger doses produced greater reductions in EHR. At 24 hours, the 5 mg dose had no residual effect, whereas other doses had intermediate residual blockade with the maximum of 50% recorded after the sustained-release 30 mg dose. The effects of the 20 mg doses were not significantly different. In study B, eight subjects randomly received at weekly intervals oral pindolol, 5 mg; intravenous pindolol, 0.045 mg/kg; oral propranolol, 80 mg; and intravenous propranolol, 0.3 mg/kg. Intravenous pindolol (0.2 mg/ml) and intravenous propranolol (1 mg/ml) were administered by Harvard pump at 1 mg/min. RHR, SHR, and EHR were measured at 0 hours (before dose) and 0.5, 1, 2, 4, 6, 8, and 24 hours after dose. No dose had any significant effect on RHR. Pindolol doses had no effect on SHR but propranolol orally and intravenously reduced SHR to about 82 bpm; the difference between the drugs was significant ( p < 0.05). The maximum effects were observed for both intravenous drugs at 0.5 hours, for oral pindolol at 1 hour, and for oral propranolol at 2 hours. The maximum effects of all four doses were similar. The effects of both pindolol doses were more sustained than those of the propranolol doses; propranolol effects declined 3.3 bpm/hr, whereas pindolol effects declined 2.1 bpm/hr. Two subjects experienced transient lightheadedness about 2 hours after doses of pindolol. The flat dose-response curve and the lack of reduction of SHR reflect the partial agonist activity of pindolol. Pindolol has high systemic bioavailability. The relative potency of oral pindolol to oral propranolol is approximately 16:1. The chronotropic beta blockade produced by pindolol declines 30% slower than that produced by propranolol.

Cardiac safety of acute beta blockade: Intrinsic sympathomimetic activity is superior to beta-1 selectivity

Regional myocardial function was assessed by multidirectional echocardiography from eight standardized segments around the left ventricle. Thirty-six subjects (healthy, severe angina pectoris, or acute myocardial infarction) were studied 15 minutes either after the beta-1-selective beta-blocking drug metoprolol had been administered in total doses of 2 and 10 mg intravenously or after pindolol, a beta blocker with intrinsic sympathomimetic activity (ISA), in total doses of 0.2 and 1.0 mg intravenously had been given. Metoprolol and pindolol reduced rate-pressure product ( p < 0.001 each), heart rate ( p < 0.001), and systolic blood pressure ( p < 0.05 to 0.001) in almost the same way. In patients with acute myocardial infarction, 0.2 mg pindolol improved ST segments by 33% and 2 mg metoprolol by 18%. Left ventricular diameter increased ( p < 0.001) and ejection fraction decreased ( p < 0.05) after metoprolol but not after pindolol. Pindolol did not reduce wall motion amplitudes of healthy myocardial segments, while metoprolol did ( p < 0.01). The overall contractile function of the left ventricle is characterized by composite segmental amplitudes from both ischemic and healthy ventricular regions. In ischemic hearts this function remained unchanged after metoprolol but improved markedly after pindolol ( p < 0.005). Thus, while intravenous pindolol and metoprolol produced equal reductions in rate-pressure product, pindolol, a beta-adrenergic-blocking drug with intrinsic sympathomimetic activity, evoked less cardiac depression and thus provided a cardiac safety factor not afforded by the beta-1-selective metoprolol.

Dependence of the cardiovascular effects of pindolol on the individual sympathetic nervous activity.

To investigate the mechanism of the relative beta-antagonist and agonist properties of pindolol, the cardiovascular effects of i.v. pindolol 0.01 mg/kg were studied in 23 subjects with different baseline levels of cardiac beta-adrenergic function. Baseline cardiac beta-adrenergic activity was assessed by the decrease in heart rate following intravenous propranolol 0.2 mg/kg (ΔHRβ) after parasympathetic blockade with intravenous atropine 0.04 mg/kg. Cardiac beta-adrenergic sensitivity was defined by the positive chronotropic effect of a three minute infusion of isoprenaline 0.005 µg/kg/min. The chronotropic effect of intravenous pindolol was negatively correlated with resting beta-adrenergic activity (R=−0.81, p<0.001). The traditional point of ΔHRβ, at which pindolol shifted from beta-antagonist to beta-agonist action, was 17 beats/min, i.e. pindolol decreased heart rate in subjects with ΔHRβ greater than 17 bpm, and increased heart rate in those with ΔHRβ less than 17 bpm. The chronotropic effect of intravenous pindolol, however, was positively correlated with beta-sensitivity (R=+0.73, p<0.001). Thus subjects with the greatest increment in heart rate with isoprenaline had an increased heart rate with pindolol, while those with the lowest increment in heart rate with isoprenaline had a decreased heart rate with pindolol. Intravenous pindolol decreased cardiac index and increased total peripheral resistance in the group with ΔHRβ more than 17 bpm, and it had the contrary actions in the group with ΔHRβ less than 17 bpm. Blood pressure in both groups was not significantly changed by pindolol. Compared to endogenous catecholamines, pindolol was considered to possess higher beta-adrenocepter affinity and weaker beta-adrenoceptor stimulating action. Therefore, pindolol produced a net beta-blocking action in subjects with elevated cardiovascular sympathetic nervous activity and beta-stimulating action in subjects with reduced sympathetic nervous activity.

Effects of pindolol on renal function.

Because beta blockers have been shown to reduce glomerular filtration rate (GFR), the renal effect of intravenous and prolonged oral administration of pindolol was examined in 10 patients with essential hypertension. Intravenous pindolol decreased inulin clearance from 99 to 94 ml/min/1.73 m2 (p < 0.005), and pulse rate from 75 to 69/min (p < 0.005). Blood pressure and filtration fraction were not changed. Oral pindolol (10 to 20 mg/day) for a mean of 6 mo resulted in a decrease in mean blood pressure from 124 to 111 mm Hg (p < 0.001), in mean pulse rate from 76 to 69/min (p < 0.005), and in mean plasma renin activity (PRA) from 0.9 to 0.29 ng/ml/hr (p < 0.05). Inulin clearance and filtration fraction did not change. At the end of oral therapy, intravenous pindolol induced a greater reduction in inulin clearance than in the first study. These observations indicate that intravenous pindolol induces a decrease in GFR probably secondary to hemodynamic effects. On the other hand, prolonged oral pindolol has no effect on GFR despite decreases in blood pressure, pulse rate, and PRA.

Clinical pharmacology of the new beta-adrenergic blocking drugs. Part 5. Pindolol (LB-46) therapy for supraventricular arrhythmia: a viable alternative to propranolol in patients with bronchospasm

Pindolol (LB-46) is a new beta-adrenoceptor blocking agent with intrinsic sympathomimetic activity. In order to evaluate the efficacy of pindolol in the treatment of patients with supraventricular arrhythmias and propranolol-induced bronchospasm, 18 patients with paroxysmal supraventricular tachycardia, atrial fibrillation, atrial flutter, multifocal atrial tachycardia or junctional tachycardia, were treated with placebo followed by pindolol in intravenous and then oral form. Following a no-response placebo period (in all patients), intravenous pindolol converted six out of seven patients with paroxysmal supraventricular tachycardia to normal sinus rhythm. In six patients with atrial fibrillation, three reverted to normal sinus rhythm, and three remained in atrial fibrillation but with a slower ventricular response (less than 100 beats/minute). Of two patients with atrial flutter, one converted to normal sinus rhythm, while the other patient failed to respond. Both patients with junctional tachycardia and one with multifocal atrial tachycardia converted to normal sinus rhythm. Long-term oral pindolol therapy sustained these responses in most patients, as documented by serial Holter ECG studies. There was no deterioration in indices of airway resistance ( FEV 1·0 VC ) in patients treated with pindolol (both intravenously and orally), in contrast to a marked deterioration in FEV 1·0 VC in the same patients treated with propranolol. Pindolol appears to be a reasonable substitute for propranolol in patients with bronchospastic illness who require beta-blockade for control of supraventricular arrhythmias.

Beta blockade with pindolol: Differential cardiac and renal effects despite similar plasma kinetics in normal and uremic man

Cardiac and renal effects (measured as the reduction in exercise-induced tachycardia and PRA, respectively) and circulating drug concentrations after acute beta blockade with intravenous pindolol were compared between seven normal volunteers and six patients with terminal renal failure. Kinetic parameters were similar in both groups (total body clearance, 450 mg/min), indicating enhanced extrarenal elimination in patients. For any given drug concentration, however, the uremic patients responded to beta blockade with a greater decrease in pulse rate than did normal volunteers (P less than 0.001). Moreover, in the same group, the decrease of PRA was more marked (from 13.3 to 5.7 vs. 3.3 to 1.9 ng/ml/hr) and lasted longer (8 hours and more vs. 2 hours). Plasma aldosterone remained unchanged. These data reveal an increased dependency of both heart rate and renin release on beta adrenergic-mediated mechanisms in uremic man. They also show that kinetic findings in normal subjects cannot always be extrapolated to predict kinetic behavior in disease, and that similar kinetics do not imply similar effectiveness.

Ocular and cardiovascular effects of local and systemic pindolol.

Ocular and cardiovascular effects of topical and intravenous pindolol have been studied in a balanced cross-0ver double-blind trial in 6 healthy volunteers. When applied to 1 eye pindolol lowered intraocular pressure in both the treated and untreated eyes with only minimal reduction in resting pupil diameter and light reflex response. The concentration in plasma was much lower and inhibiton of exercise tachycardia about half that when the same dose was administered intravenously. The findings suggest that beta-adrenoceptor blocking drugs should not be used in the treatment of glaucoma in patients who also suffer from heart failure.

Electrophysiologic effects of pindolol on atrioventricular conduction in canine heart.

The effects of intravenous pindolol on the electrophysiologic properties of the atrioventricular conduction system was studied in intact dog, using His bundle electrogram and the extrastimulus method. Pindolol was administered intravenously in a dose range of 4 to 40 micrograms/Kg. The latter dosage of pindolol is above those used clinically. Significant effects of intravenous pindolol were observed on sinus cycle length, the A-V nodal conduction time, the ERP of the atrium, the ERP and FRP of the A-V node, and the ERP of the ventricle. Sinus cycle length was prolonged during sinus rhythm. Intraatrial conduction time was not altered by pindolol, while the ERP of the atrium was slightly increased. The A-H interval was generally prolonged by pindolol without Wenckebach type A-V block, but the H-V interval was unchanged. Both ERP and FRP of the A-V node was prolonged. The ERP and RRP of the His-Purkinje system were not statistically evaluated, because no block within the His-Purkinje system were not statistically evaluated, because no block with the His-Purkinje system or prolongation of H-V interval was produced and only a few QRS complexes by extrastimulus showed aberrant configration in the intact canine heart. In addition, pindolol prolonged the ERP of the ventricle.

Pharmacokinetics of Intravenous and Oral Pindolol in Hypertensive Patients with Chronic Renal Failure

1. The pharmacokinetics of intravenous and oral pindolol were determined in 24 hypertensive patients with normal or impaired renal function. 2. In patients with normal renal function, the total clearance of the drug was the sum of both the renal and non-renal clearances in equal parts. The non-renal clearance was found to equal the hepatic clearance directly measured from the hepatic extraction ratio and hepatic blood flow. 3. Compared with patients with normal renal function, patients with chronic renal failure exhibited (i) unchanged transfer rate constants and distribution volumes, (ii) decreased total body clearance with decreased renal clearance and unchanged non-renal clearance. 4. Analysis of data obtained after oral administration of the drug by the Loo-Riegelman method showed that the pindolol absorption kinetic was non-linear. Compared with patients with normal renal function, patients with chronic renal failure exhibited (i) a significantly decreased fraction of dose effectively absorbed, (ii) an increased initial rate of absorption. The initial rate of absorption was inversely correlated with creatinine clearance. 5. The study provided evidence that in patients with renal insufficiency, (i) no increase in the metabolism of the drug accompanied the decrease in renal function, and (ii) decreased bio-availability was associated with a reduced fraction of the dose effectively absorbed and an increased rate of absorption.

PROFILE OF β‐ADRENOCEPTORS IN FEMORAL, SUPERIOR MESENTERIC AND RENAL VASCULAR BEDS OF DOGS

1. The homogeneity of beta-adrenoceptors in femoral, superior mesenteric and renal vascular beds was investigated by the use of the regional perfusion technique in dogs. 2. Isoprenaline and salbutamol produced dose-related increases in femoral and superior mesenteric blood flow. The dose-response curves for the two agonists were parallel, but salbutamol was approximately 1/15 as potent as isoprenaline on a weight basis. 3. Isoprenaline and salbutamol increased renal blood flow in a dose-related manner. However, salbutamol was approximately 1/240 as potent as isoprenaline on a weight basis, and the slope of the dose-response curve for salbutamol was less steep than that for isoprenaline. 4. The dose-response curves to isoprenaline for increase in femoral and superior mesenteric blood flow were shifted to the right by intravenous pindolol but not by intravenous or intra-arterial practolol. 5. The dose-response curves to isoprenaline for increase in renal blood flow were shifted to the right more markedly by intravenous pindolol than by intravenous or intra-arterial practolol. 6. The results indicate that beta-adrenoceptors of the renal vascular bed consist of beta1-type and beta2-type whereas the femoral and superior mesenteric vascular beds contain only beta2-adrenoceptors.