Direct toxicity

This hypothesis states that direct adverse effects of beta₂‐agonists are responsible for an associated increase in mortality and most research in the area has concentrated on effects detrimental to the heart. Whilst it is often assumed that cardiac side‐effects of beta₂‐agonists are due to cross‐reactivity with beta₁‐adrenoceptors (i.e. poor selectivity), it is worth noting that human myocardium also contains an abundance of beta₂‐adrenoceptors capable of triggering positive chronotropic and inotropic responses (Lipworth 1992).  Indeed, there is good evidence that cardiovascular side‐effects of isoprenaline (Arnold 1985) and other beta₂‐agonists including salbutamol (Hall 1989) are mediated predominantly via cardiac beta₂‐adrenoceptors thus making the concept of in vitro selectivity less relevant. Generalised beta₂‐adrenoceptor activation can also cause hypokalaemia (Brown 1983) and it has been proposed that, through these and other actions beta₂‐agonists may predispose to life‐threatening dysrhythmias or cause other adverse cardiac effects.

During the 1960s epidemic most deaths occurred in patients with severe asthma and it was originally assumed that asthma and its sequelae, including hypoxia, were the primary cause of death.  However, mucus plugging and hypoxia does not preclude a cardiac event as the final cause of death, and one might expect those with severe asthma to take more doses of a prescribed inhaler. As noted by Speizer and Doll most deaths in the 1960s were in the 10‐19 age group and “at these ages children have begun to act independently and may be particularly prone to misuse a self‐administered form of treatment” (Speizer 1968).  If toxicity were related to increasing doses of beta₂‐agonists one might expect most deaths to occur in hospital where high doses are typically used and this was not the case. One possible explanation for this anomaly was provided by animal experiments in which large doses of isoprenaline caused little ill effect in anaesthetised dogs with normal arterial oxygenation whereas much smaller doses caused fatal cardiac depression and asystole (although no obvious dysrhythmia) when hypoxic (Collins 1969; McDevitt 1974).  It has been hypothesised therefore that such events would be less likely in hospital where supplemental oxygen is routinely given. The clinical relevance of these studies remains unclear although there is some evidence of a synergistic effect between hypoxia and salbutamol use in asthmatic patients in reducing total peripheral vascular resistance (Burggraaf 2001) – another beta₂ mediated effect which could be detrimental to the heart during an acute asthma attack through a reduction in diastolic blood pressure.  Other potential mechanisms of isoprenaline toxicity include a potential increase in mucous plugging and worsening of ventilation perfusion mismatch despite bronchodilation (Pearce 1990).

Further concerns about a possible toxic effect of beta₂‐agonists were raised during the New Zealand epidemic in the 1970s.  In 1981 Wilson et al, who first reported the epidemic, reviewed 22 fatal cases of asthma and noted “In 16 patients death was seen to be sudden and unexpected.  Although all were experiencing respiratory distress, most were not cyanosed and the precipitate nature of their death suggested a cardiac event, such as an arrest, inappropriate to the severity of their respiratory problem” (Wilson 1981). In humans, fenoterol causes significantly greater chronotropic, inotropic and electrocardiographic side‐effects than salbutamol in asthmatic patients (Wong 1990).  Interestingly, across the same parameters fenoterol also causes more side‐effects than isoprenaline (Burgess 1991). 

In patients with mild asthma and without a bronchoconstrictor challenge, salmeterol and salbutamol cause a similar degree of near maximal bronchodilation at low doses (Bennett 1994). However, whilst as a one off dose salbutamol is typically used at 2‐4 times the concentration of salmeterol, the dose equivalences for salmeterol versus salbutamol in increasing heart rate and decreasing potassium concentration and diastolic blood pressure were 17.7, 7.8 and 7.6 respectively (i.e salmeterol had a greater effect across all parameters).  Given the lower intrinsic efficacy of salmeterol (Table 1), these results highlight the importance of in vivo factors; one possible explanation for the difference is the increased lipophilicity of salmeterol compared to salbutamol contributing to higher systemic absorption (Bennett 1994).    

When comparing increasing actuations of standard doses of formoterol and salmeterol inhalers in stable asthmatic patients, relatively similar cardiovascular effects are seen at lower doses (Guhan 2000).  However, at the highest doses (above those recommended by the manufacturers) there were trends towards an increase in systolic blood pressure with formoterol;  in comparison there was a trend towards a decrease in diastolic blood pressure and an increase in QTc interval with salmeterol although no statistical analysis of the difference was performed.  In contrast in asthmatic patients with methacholine‐induced bronchoconstriction there was no significant difference between salmeterol and formoterol in causing increased heart rate and QTc interval although formoterol caused significantly greater bronchodilation and hypokalaemia (Palmqvist 1999). Whilst there is good evidence of cardiovascular and metabolic side‐effects with increasing doses of beta₂‐agonists, it is a little difficult to envisage serious adverse effects of this nature when using LABAs at manufacturer‐recommended preventative doses.  However, it is possible that some patients choose to use repeated doses of LABAs during exacerbations. 

Tolerance

In this setting, the term tolerance refers to an impaired response to beta₂‐agonists in patients who have been using regular beta₂‐agonist treatment previously (Haney 2006). Tolerance is likely to result from a combination of reduced receptor numbers secondary to receptor internalisation and reduced production and also uncoupling of receptors to downstream signalling pathways following repeated activation (Barnes 1995). This phenomenon is likely to explain the beneficial reduction in systemic side effects seen with regular use of beta₂‐agonists including salbutamol after 1‐2 weeks (Lipworth 1989). However, the same effect on beta₂‐adrenoceptors in the lung might be expected to produce a diminished response to the bronchodilating activity of beta₂‐agonists following regular use. In patients with stable asthma, whilst there is some evidence of tolerance to both salbutamol (Nelson 1977) and terbutaline (Weber 1982) other studies have been less conclusive (Harvey 1982; Lipworth 1989).  However, evidence of tolerance to short and long‐acting beta₂‐agonists in both protecting against and reducing bronchoconstriction is much stronger in the setting of an acute bronchoconstrictor challenge with chemical, allergen and 'natural' stimuli ( Haney 2006; Lipworth 1997). 

Studies comparing salmeterol and formoterol have shown that both cause tolerance compared to placebo but there was no significant difference between the drugs (van der Woude 2001).  There also appears to be little difference in the tolerance induced by regular formoterol and regular salbutamol treatment (Hancox 1999; Jones 2001).  To the authors' knowledge no studies have looked specifically at the degree of tolerance caused by isoprenaline and fenoterol in the setting of acute bronchoconstriction. Tolerance to bronchodilation has been shown to clearly occur with addition of inhaled corticosteroids to salmeterol and formoterol (Lee 2003) and terbutaline (Yates 1996).  There is conflicting evidence as to whether high dose steroids can reverse tolerance in the acute setting ( Jones 2001; Lipworth 2000).

At first glance the toxicity and tolerance hypotheses might appear incompatible as systemic and cardiovascular tolerance ought to protect against toxicity in the acute setting and there is good evidence that such tolerance occurs in stable asthmatic patients (Lipworth 1989).  However, whilst this study showed that changes in heart rate and potassium levels were blunted by previous beta₂‐agonist use, they were not abolished; furthermore, at the doses studied these side‐effects appear to follow an exponential pattern (Lipworth 1989).  In contrast, in the presence of bronchoconstrictor stimuli the bronchodilator response to beta₂‐agonists follows a flatter curve ( Hancox 1999; Wong 1990) and as previously discussed this curve is shifted downwards by previous beta₂‐agonist exposure (Hancox 1999).  Thus, it is theoretically possible that in the setting of an acute asthmatic attack and strong bronchoconstricting stimuli, bronchodilator tolerance could lead to repetitive beta₂‐agonist use and ultimately more systemic side‐effects than would otherwise have occurred.  Of course, other sequelae of inadequate bronchodilation including airway obstruction will be detrimental in this setting.

Whilst the tolerance hypothesis is often cited as contributing towards the asthma mortality epidemics it is difficult to argue that reduced efficacy of a drug can cause increased mortality relative to a time when that drug was not used at all.  However, tolerance to the bronchodilating effect of endogenous circulating adrenaline is theoretically possible and there is also evidence of rebound bronchoconstriction when stopping fenoterol (Sears 1990), which may be detrimental.  Furthermore, it appears that regular salbutamol treatment can actually increase airway responsiveness to allergen (Cockcroft 1993) a potentially important effect that could form a variant of the toxicity hypothesis.  Differences between beta₂‐agonists in this regard are unclear, but the combination of rebound hyperresponsiveness and tolerance of the bronchodilator effect with regular beta₂‐agonist exposure has been recently advocated as a possible mechanism to explain the association between beta₂‐agonists and asthma mortality (Hancox 2006a).

Other explanations

Reduced corticosteroid treatment

A slight but significant variation of the delay hypothesis suggests that patients who have separate beta₂‐agonists and corticosteroid inhalers may choose to take less corticosteroid because of better symptom control from the inhaled beta₂‐agonists and it is reduced corticosteroid treatment that contributes to a rise in mortality.  It is rather difficult to see how this hypothesis explains the epidemics of asthma deaths in the 1960s and 1970s relative to the 1920s and 30s (Figure 5), given that corticosteroids were not used for the treatment of asthma in the earlier decades.  If this hypothesis were to explain increased mortality from more recent randomised controlled trial data one would not expect to see an increase in mortality in those taking LABAs alone. 

Figure 5

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Changes in asthma mortality (5‐34 age group) in three countries in relation to the introduction of isoprenaline forte in the UK and New Zealand and of fenoterol in New Zealand. (From Blauw 1995. With permission from the Lancet).