Beta-Adrenergic Blockade with Pindolol (LB-46) in Mild to Moderate Asthma Observations

Acceptable beta-adrenergic antagonists for use in patients with asthma should ideally minimize antagonism of bronchial (beta2) receptors while providing useful cardiac (beta2) blockade. Propranolol, a nonselective beta-adrenergic blocking drug, aggravates bronchospasm in asthmatics. Metoprolol, a selective betai blocker approved for use in the United States, may have decreased effect on the airways. However, its selectivity is thought to be dose-related and perhaps limited to the lower dose ranges.

Pindolol (LB-46), a potent beta-adrenergic blocker, does not have selective betai antagonism and is said to have intrinsic sympathomimetic activity. Whether or not this activity is responsible for any relative sparing of beta2-adrenergic receptors, it is suggested that pindolol may be better tolerated in asthma and other obstructive lung diseases than other beta-adrenergic blockers.

Pulmonary Spirometric Studies

Previously reported studies have been contradictory. One study using 0.4 mg of pindolol administered intravenously showed that the FEVi was not reduced, whereas 5 mg of propranolol lowered the FEVi in the same subjects. Gavrilescu, after IV administration of 0.5 mg pindolol, found no reduction of the preinfusion FEVi in asthmatics. Beumer and Hardonk reported on six asthmatic subjects who were given 1 mg or 2 mg of pindolol intravenously. No difference from placebo was found in the FEVi, but the subjects were said to have only “latent asthma” in remission. In another study of 20 asthmatics, some of whom were moderately severe by spirometric and clinical criteria, a single 5 mg oral dose of pindolol did not significantly reduce FEVi or VC compared to placebo. However, two subjects had marked falls in FEV1, and there was no significant increase in FEVi after salbutamol inhalation on the day that pindolol was given. Finally, 18 patients with supraventricular tachyarrhythmias who had propranolol-induced bronchospasm documented by pulmonary spirometric studies, were given pindolol orally and intravenously. The nine patients whose spirometric data were reported showed no change in FEVi/VC after at least 0.4 mg of pindolol administered intravenously. Some of these patients had moderately severe obstruction, with four having FEVi/VCS of less than 50 percent.

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However, Benson et al presented five asthmatic subjects whose FEVi decreased by more than 20 percent after receiving one or more beta-adrenergic blockers. In these five subjects, 5 mg of pindolol given orally caused a significant decrease (P< 0.01) in FEVi compared to placebo. There was also a smaller response to isoproterenol inhalation (P < 0.05). Mattson and Poppius tested four patients with severe asthma within 15 days of an admission for acute asthma. All required corticosteroid treatment, but all had FEVi greater than 50 percent of predicted on the test day. All four subjects given 0.2 mg of pindolol intravenously reported chest tightness, while the FEVi fell 15-27% and the SGaw fell 28-74$. No improvement in FEVi was reported in three subjects then given isoproterenol.

Heart Rate

We found that pindolol, given in a fixed dose of 0.4 mg intravenously, produced betai-adrenergic blockade as measured by reduction in exercise heart rate, although resting heart rates were not significantly different. This is similar to the findings of Gugler et al. Our decrease in mean maximal exercise heart rate with 0.4 mg of pindolol, 26 beats per minute, is close to the 29 beats per minute determined by Epstein et al in normal subjects given 0.15 mg/kg of propranolol intravenously, suggesting a comparable degree of beta-adrenergic blockade. Despite this, the maximal V02 was only slightly less on pindolol compared with placebo, suggesting a comparable degree of exercise. At this dose, no significant differences were found between pindolol and placebo in the resting or postexercise pulmonary function, although there was a general trend of decreased pulmonary function in the pindolol postexercise studies. No asthmatic attacks were precipitated, and we could find no differences in asthma symptoms. The response to isoproterenol following testing, however, was significantly different for FEVi and PEFR, suggesting perhaps that treatment with bronchodilator drugs might be impaired. Nevertheless, these differences were small between pindolol and placebo, and both groups showed significant improvement on all tests analyzed following isoproterenol.

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Resting postdrug studies alone may be too insensitive to detect drug-induced differences. Although there were no significant differences between placebo and pindolol after exercise, easily measurable declines in pulmonary function were seen in both groups. We feel that exercise is both a more relevant physiologic stimulus to bronchospasm in asthmatics than other methods, and also a relatively safe way of increasing the sensitivity of pulmonary function measurements when testing drugs that potentially affect the airways.

The dose of pindolol that we used was the same for all subjects. Thus, no conclusion about larger doses of pindolol are warranted, and a dose-dependent potentiation of bronchospasm cannot be excluded. In addition, we consider the subjects tested to have mild to moderate asthma in remission. Therefore, no conclusions about the relative safety of pindolol in more severe asthma or during acute attacks should be made. In this we are in agreement with Mattson and Poppius who suggest that because of the effect of varying intrinsic sympathetic tone, individual and temporal differences in airway response must be considered when evaluating the effect of beta-adrenergic agonists and antagonists. The clinical phase of asthma may be important as well, since only one study challenged relatively unstable patients with pindolol. We conclude that our beta-blocking dose of pindolol may be tolerated by mild to moderate asthmatic subjects in remission, but maximum bronchodilator therapy may be compromised.