Canadian Health and Care Mall: Discussion of Inhaled Salbutamol in Humans

The cardiac electrophysiologic effectsDespite the widespread use of β 2-agonists, their safety has been questioned. Several studies have reported an increased incidence of cardiac arrhythmias in patients treated with these agents, and other studies found an increased cardiovascular death with the use of oral and nebulized β2-agonists. Although no causal relationship has been demonstrated, the possible arrhythmogenic effects of these drugs place them under considerable suspicion. Clarifying the effects of β2-agonists on myocardial conduction and refractoriness could provide a significant insight into the potential arrhythmogenic role of these agents. This study is the first to evaluate the cardiac electrophysiologic effects of a single, regular dose of an inhaled β 2-agonist in humans. Salbutamol was selected, as it is one of the most widely used inhaled β2-agonists and would ensure improved correlation with standard clinical practice. The main finding of this study is that the inhalation of a standard dose of the β2-agonist salbutamol results in significant changes of cardiac electrophysiologic properties.

We found that inhalation of a single regular dose of salbutamol significantly enhanced AV nodal conduction, as reflected by shortening of the AH interval and decreased atrial and ventricular refractoriness without any remarkable effect on His-Purkinje conduction. The refractoriness of the AV node was also decreased, as indicated by shortening of the atrial pacing cycle length that resulted in AV node Wenckebach block. In addition, inhaled salbutamol produced a significant increase in heart rate and shortened the SNRT.

However, our findings cannot be interpreted on the basis of changes in heart rate. Since all refractory periods were determined at the same drive cycle length (both 500 ms and 400 ms), the observed changes in refractory periods are independent of the underlying heart rate and indicate the effects of salbutamol on myocardial conduction and refractoriness. Moreover, we found a shortening of the AH interval after the inhalation of salbutamol, which seems to be due to the effect of the drug, as the AH interval normally decreases with a sympathetic driven heart rate increase. The source: canadian health care mall gives you an opportunity to enter the world of medicine and pharmacy.

Human heartThe above electrophysiologic effects of salbutamol are in accordance with the known cellular effects of the P-adrenergic stimulation (shortening of the action potential duration in the nodes and in atrial and ventricular muscle, increase in upstroke velocity of the action potential in the AV node, and no effect on the upstroke velocity of the action potential in the His-Purkinje system or ventricular myocardium). Therefore, our findings could be explained by a direct activation of P2-adrenergic receptors.

It has indeed been increasingly recognized that P1- and P2-adrenergic receptors coexist in the human heart. P2-adrenergic receptors constitute 20 to 30% and 30 to 40% of the total number of P-adrenergic receptors in human ventricles and atria, respectively. In addition, salbutamol, a selective P2-agonist, would not be expected to stimulate P-adrenergic receptors under the conditions applied. Furthermore, salbutamol in our study produced a greater proportional decrease in atrial tissue refractoriness compared with the ventricular tissue refractoriness. These differential effects on atrial and ventricular refractoriness could be explained by the different density of P2-adrenergic receptors in atrial and ventricular myocardium, suggesting that the effects of salbutamol were mediated by direct activation of these receptors.

The activation of prejunctional P2-adrenoceptors leading to an enhanced noradrenaline release and indirect stimulation of ^-adrenergic receptors is also unlikely. The intracoronary infusion of salbuta-mol caused significant changes on temporal dispersion of cardiac repolarization, and no blunting of these effects in patients receiving the ^-selective adrenergic receptor antagonist, atenolol, was noted in one study. In another study, intracoronary injection of salbutamol caused increases in heart rate that were not affected by the ^-adrenoceptor antagonist practolol but were blocked by the nonselec-tive P-adrenoceptor antagonist propranolol.

Salbutamol produced similar effectsReflex release of catecholamines secondary to P2-adrenergic receptor-mediated peripheral vasodilatation is not likely to influence our findings, as no measurable changes to systolic or to diastolic BP were observed. Moreover, in heart transplant recipients after pretreatment with the P1-adrenoceptor antagonist bisoprolol, isoprenaline is found to increase heart rate under conditions where it acts solely via P2-adrenergic receptors, an effect that cannot be due to any reflex mechanisms since the transplanted human heart is a denervated organ.

The results of our study demonstrate that salbuta-mol, a selective P2-agonist, administered by nebulizer has significant electrophysiologic effects on the atrium, nodes, and ventricle. The dosages administered reflected the regular recommended clinical dose, emphasizing that our findings are of particular importance since there is significant correlation with the everyday clinical practice. Larger doses of salbu-tamol, such as those used in asthmatic exacerbations, could have led to even more pronounced changes in myocardial conduction and refractoriness.

Comparison With Other Studies

Existing data on the effects of P2-agonists, especially those administered in an inhaled form, on myocardial electrophysiologic properties are rare. In a previous experimental study, inhaled metaprot-erenol, a P2-agonist, resulted in significant enhancement of AV node conduction and a decrease of cardiac tissue refractoriness in dogs. In a more recent human study, salbutamol produced similar effects but was administered IV. In general, our findings are in agreement with the results of the above-mentioned studies.

Diastolic BPThere are, however, some significant differences. First, our study is the first to evaluate the effects of an inhaled, selective P2-agonist on AV node conduction and myocardial tissue refractoriness in humans. Secondly, the administration mode of salbutamol correlates well with everyday clinical conditions. In addition, unlike the study by Insulander et al, we found no measurable changes in systolic or diastolic BP after the administration of salbutamol, suggesting that no reflex mechanism influenced our findings. This could be explained by the fact that inhaled salbutamol has significantly fewer systemic effects than salbutamol one. Especially, in our study the proportional decrease of atrial refractory period after salbutamol inhalation was greater than the ventricular refractory period decrease, which is consistent with the different density of P2-adrenergic receptors in atrial and ventricular myocardium. Finally, salbu-tamol in our study produced more evident changes on the sinus node electrophysiologic properties compared with AV node. This finding is in contrast with the results of Insulander et al, but confers with the recently published study by Rodefeld et al, which shows that β 2-adrenoceptor density is about 2.5-fold higher in the human sinoatrial node than in the right atrial myocardium.

Clinical Implications

The cardiac effects of 2-agonists include tachycardia, atrial and ventricular ectopic complexes, as well as atrial and ventricular arrhythmias. Our study allows us to speculate that the shortening of the cardiac tissue refractoriness may facilitate the induction of such arrhythmias and could explain the increased incidence of arrhythmias in certain patients receiving β 2-agonists. It is well known that the decrease in tissue refractoriness predisposes reentrant and triggered arrhythmias. This could be particularly important in certain clinical conditions, such as heart failure. The down-regulation of the P1-receptors in chronic heart failure results in relative up-regulation of the cardiac P2-receptors. As a consequence, β 2-agonists may produce significantly greater cardiac electrophysiologic changes in patients with compromised cardiac function, predisposing to atrial and ventricular arrhythmias. There is evidence that salbutamol increases the episodes of ventricular tachycardia in patients with heart fail-ure and that β 2-receptor antagonists protect against ventricular fibrillation in animals shown to be susceptible to malignant arrhythmias. Furthermore, the decreases of AV node conduction time and refractoriness produced by salbutamol could result in an increase of the ventricular response during certain supraventricular arrhythmias such as atrial flutter and fibrillation.

Electrophysiologic effectsStudy Limitations

The design of our study does not allow as to evaluate the role of the β – adrenergic system in mediating the electrophysiologic effects of salbuta-mol. Moreover, there are no selective (32-receptor antagonists available for use in vivo that would permit us to estimate the selectivity of the action of salbutamol. In any case, salbutamol is a selective P2-agonist; as noted previously, our findings seem to be independent of any reflex mechanism.

The results of our study refer to the acute effects of inhaled salbutamol. Although our study assessed the short-term effects, as opposed to the long-term effects, the existing evidence of down-regulation of extrapulmonary β2-receptors (including cardiac receptors) after prolonged administration of β2-ago-nists suggests that the effects are likely to be more marked in patients who are not receiving these agents continuously.

Conclusion

We have demonstrated that inhaled salbutamol results in significant changes in cardiac electrophysi-ologic properties. These effects seem to be due to P2-adrenergic stimulation and could explain the increased incidence of arrhythmias in some patients treated with these agents, especially in certain clinical conditions, such as heart failure. Care must be taken before extrapolating our findings to all human subjects, and further studies are required to clarify to what extent the electrophysiologic effects of salbuta-mol contribute to the generation of spontaneous arrhythmias.

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