Isoprenaline

The [Beta]-agonists are the most widely prescribed drugs for the treatment of airways obstruction. While their efficacy as symptom relievers is unquestioned, there has been considerable debate about the safety of their regular long-term use in patients with asthma, and there are much fewer data concerning possible side effects in patients with COPD. Indeed, in the recent British Thoracic Society guidelines,[1] which recommend inhaled [Beta]-agonists as "the cornerstone of symptomatic treatment for the reversible component of airway obstruction" in COPD (both for regular use and by nebulizer for acute exacerbations), there is little mention of potential side effects; in particular, possible cardiac effects are not listed. On the face of it, this is surprising, particularly because the majority of these patients are hypoxemic and therefore possibly susceptible to unwanted cardiac effects.

Interaction between [Beta]-agonists and specific receptors leads to an activation of adenylyl cyclase and a reduction of intracellular calcium.[2] However, it has recently been reported that such drugs may also induce an influx of calcium into smooth muscle cells, by virtue of effects that are unrelated to [Beta]-adrenoceptor occupancy and that are not accompanied by activation of adenylyl cyclase.[3,4] Whether these anomalous effects of [Beta]-sympathomimetics can also be manifest in cardiac tissue is unknown. It is recognized that inotropic or chronotropic effects of salbutamol are minor but that during myocardial hypoxia ischaemic myocardial necrosis occurs.[5]

Early studies with isoproterenol demonstrated that hypoxemia increased its cardiotoxic effects[6] and that severe hypoxemia ([PaO.sub.2], 40 mm Hg [5.3 kPa]) causes a marked increase in heart rate and stroke volume[7] in the dog. Studies in man show that the chronotopic response to salbutamol is increased by hypoxemia.[8] [[Beta].sub.2]-Agonist inhalation in patients with COPD causes pulmonary arterial vasodilation; the consequent increase in ventilation/perfusion mismatch leads to a small fall in systemic [PaO.sub.2].[9] The clinical significance of these changes is dubious, although clearly the pretreatment [PaO.sub.2] is important. Furthermore, patients with hypoxemic COPD may have a subclinical autonomic neuropathy with a prolonged electrocardiographic QTc interval and the consequent risk of ventricular dysrhythmia and sudden death.[10] [Beta]-Agonists, and in particular fenoterol, may increase the QTc interval post nebulization, and this combined with the chronotopic and hypokalemic effects may contribute to the phenomenon.[11] It is postulated that people with prolonged stress QTc intervals, particularly with autonomic dysfunction, might be at greater risk of a fatal dysrhythmia with high-dose nebulized [Beta]-agonists. The combination of a xanthine derivative and a [Beta]-agonist in these patients may increase the risk.[12]

All of this may suggest that [Beta]-agonists should be used with caution in patients with hypoxemia due to COPD. Furthermore, most of these patients are smokers and of an older age and, therefore, more likely to have coexistent ischemic heart disease. There are, however, few clinical data to suggest that the use of [Beta]-agonists may have adverse effects in patients with stable COPD. Seider et al[13] concluded that no dear relation could be established between inhaled nebulized bronchodilators and cardiac dysrhythmias in patients with COPD and ischemic heart disease. However, the study from Cazzola and colleagues in this issue (see page 411) to compare the use of the long-acting [Beta]-agonists formoterol (at two dose levels) and salmeterol in COPD patients with pre-existing arrhythmias and hypoxemia counsels some caution. They report that higher dose formoterol had a more marked effect on rate, rhythm, and hypokalaemia than lower dose formoterol, salmeterol, or placebo in this vulnerable group of patients. In a previous study, formoterol had fewer cardiovascular effects than fenoterol.[14]

How should the clinician use these drugs in COPD patients? Clearly they are useful for symptomatic benefit, and potential adverse effects on bronchial inflammation and hyperresponsiveness that may be relevant in asthma are not, as far as we know, clinically important in COPD, although regular bronchodilator treatment may accelerate the decline in lung function in these patients.[15] Nevertheless, the combination of dysrhythmiagenesis and hypokalemia in hypoxic patients with cardiac rhythm and autonomic disturbances should make the prescriber think carefully before prescribing these agents, especially at high dosage. Any new symptoms, such as chest pain, syncope, or palpitations, that the patient suggests may be related to their [Beta]-agonist medication should be investigated, and the treatment adjusted accordingly. Although it has been suggested that oral or nebulized [Beta]-agonists should be avoided altogether in patients with "significant cardiac disease or high risk for such disease,"[16] this argument cannot be applied to all forms of [Beta]-agonist therapy, whose symptomatic benefits in responsive patients should, as the British Thoracic Society guidelines recommend, continue to make them the most important group of drags for the treatment of disabling dyspnea in COPD.

REFERENCES

[1] British Thoracic Society Guidelines for the Management of Chronic Obstructive Pulmonary Disease. Thorax 1997; 52. Supplement 5

[2] Barnes PJ. Beta-adrenergic receptors and their regulation. Am J Respir Crit Care Med 1995; 152:838-60

[3] Muraki K, Bolton TB, Imaizumi Y, et al. Receptor for catecholamines responding to catechol which potentiates voltage-dependent calcium current in single cells from guinea-pig taenia caeci. Br J Pharmacol 1994; 111:1154-62

[4] Mitra S, Ugur M, Ugur O, et al. (S)-Albuterol increases intracellular free calcium by muscarinic receptor activation and a phospholipase C-dependent mechanism in airway smooth muscle. Mol Pharmacol 1998; 53:347-54

[5] Libretto SE. A review of the toxicology, of salbutamol (albuterol). Arch Toxicol 1994; 68:213-16

[6] Collins JM, McDevitt DG, Shanks RG, et al. The cardiotoxicity of isoprenaline during hypoxia. Br J Pharmacol 1969; 36:35-45

[7] Kontos HA, Levasseuer JE, Richardson DW, et al. Comparative circulatory responses to systemic hypoxia in man and in unanaesethised dogs. J Appl Physiol 1969; 23:381-86

[8] Leitch AG, Clancy LJ, Costello JF, et al. Effect of intravenous infusion of salbutamol on ventilatory response to carbon dioxide and hypoxia and on heart rate and plasma potassium in normal men. Brit Med J 1976; 1:365-67

[9] Cazzola M, Spina D, Matera MG. The use of bronchodilators in stable chronic obstructive pulmonary disease. Pulm Pharmacol Ther 1997; 10:129-44

[10] Stewart AG, Waterhouse JC, Howard P. The [QT.sub.c] interval, autonomic neuropathy and mortality in hypoxaemic COPD. Respir Med 1995; 89:79-84

[11] Bremner P, Burgess CD, Crane J, et al. Cardiovascular effects of fenoterol under conditions of hypoxemia. Thorax 1992; 47:814-17

[12] Conradson TB, Eklundh G, Olofsson B, et al. Cardiac arrhythmias in patients with mild-to-moderate obstructive lung disease: comparison of beta-agonist therapy alone and in combination with a xanthine derivative, enprofylline or theophylline. Chest 1985; 88:537-42

[13] Seider N, Abinader EG, Oliven A. Cardiac arrhythmias after inhaled bronchodilators in patients with COPD and ischemic heart disease. Chest 1993; 104:1070-74

[14] Bremner P, Woodman K, Burgess C, et al. A comparison of the cardiovascular and metabolic effects of formoterol, salbutamol and fenoterol. Eur Resp J 1993; 6:204-10

[15] van Schayck CP, Dompeling E, van Herwaaden CL, et al. Bronchodilator treatment in moderate asthma or chronic bronchitis: continuous or on demand? A randomised controlled study. BMJ 1991; 303:1426-31

[16] Suissa S, Hemmelgarn B, Blais L, et al. Bronchodilators and acute cardiac death. Am J Resp Crit Care Med 1996; 154:1598-609.

Department of Respiratory Medicine, Kings College School of Medicine and Dentistry.

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