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Bronchodilation and Bronchoprotection

Formoterol is a more potent bronchodilator than salmeterol in vitro (19). This difference is also evident in vivo (57), as formoterol causes similar bronchodila-tion compared to salmeterol but at lower doses. Another important difference between these two drugs is the onset of action; formoterol has a faster onset

Figure 5 Time course of bronchodilation with short- and long-acting b-agonists. Increase in FEV1 over 12 hours after inhalation of salbutamol 200 mg (triangles), sal-meterol 50 mg (squares) and formoterol 12 mg (circles). Formoterol and salbutamol have a faster onset of action compared to salmeterol. The effects of formoterol and salmeterol last for 12 hours. Source: From Ref. 27.

Figure 5 Time course of bronchodilation with short- and long-acting b-agonists. Increase in FEV1 over 12 hours after inhalation of salbutamol 200 mg (triangles), sal-meterol 50 mg (squares) and formoterol 12 mg (circles). Formoterol and salbutamol have a faster onset of action compared to salmeterol. The effects of formoterol and salmeterol last for 12 hours. Source: From Ref. 27.

with significant smooth muscle relaxation occurring within five minutes (Fig. 5). Using the doses commonly prescribed in clinical practice, the duration of bronchodilation for a single dose of salmeterol or formoterol is similar with therapeutic effects lasting for approximately 12 hours (27,58,59).

LABA protect against bronchoconstricting stimuli such as methacho-line, histamine, and AMP (20,32,60-62). For salmeterol, maximal bronchoprotection is achieved after a single dose of 50 mg (20), and increasing the dose further provides no extra bronchoprotection (Fig. 6). A similar level of bronchoprotection is observed after a single 12 mg formoterol dose, but unlike salmeterol, further increases in the dose of formoterol result in greater bronchoprotection. This difference in dose-responsiveness is attributable to the pharmacological differences between the two drugs in their interactions with the p2-AR.

LABA and b2-AR Tolerance

Regular LABA therapy may cause p2-AR desensitization. This effect may manifest as a reduction in bronchodilation or bronchoprotection.

Bronchodilator Tolerance

Studies of regular LABA use for up to one year in duration have shown no deterioration in pulmonary function (58,63,64). This suggests that broncho-dilator tolerance during regular LABA therapy is not an important clinical doubling doses mch

Salmeterol

Formoterol

Salmeterol

dose 1 Fo 12 Sm 50

dose 2 Fo 60 Sm 250

dose 3 Fo 120 Sm 500

Figure 6 Dose-response effect of formoterol (Fo) and salmeterol (Sm) on PD2o methacholine. There was no difference between Fo 12 mg and Sm 50 mg (p = 0.70). Higher Fo doses increased PD20 values, while there was no change with higher Sm doses. Significant differences between doses two and three in bronchoprotection were observed (p < 0.01). Source: From Ref. 20.

issue. However, studies assessing tolerance to the effects of a SABA during regular LABA therapy have produced conflicting results. The bronchodilator response to cumulative doses of albuterol were found to be reduced at 36 hours after stopping salmeterol (65) and at 24 hours after stopping formoterol (66). The acute bronchodilator effects of formoterol, itself administered in a cumulative dosing regime, are also reduced after regular dosing with for-moterol (67,68). In contrast, other studies have not found the bronchodilator response to albuterol to be blunted during regular LABA therapy (69-71). These studies have been criticized for an inadequate LABA washout period before the assessment of the albuterol response, i.e., the albuterol response was assessed within 12 hours of the last dose of LABA, which would increase the prealbuterol FEV1, making it difficult to study the bronchodilator response (66). However, it is clear that assessing albuterol within 12 hours of a dose of LABA more accurately simulates the use of SABA in clinical practice. Taken together, these data make it likely that bronchodilator tolerance during regular LABA use is of limited clinical importance.

Tolerance to Bronchoprotection

Regular LABA treatment can reduce the degree of bronchoprotection without a decrease in bronchodilation. For example, salmeterol causes a 10-fold increase in methacholine PC2o on the first day of treatment, but this declines to a twofold increase at four and eight weeks despite no change in bronchodilator effect (72). This reduction in bronchoprotection against methacholine can be observed after just two doses of salmeterol (73), and occurs irrespective of the concurrent administration of standard doses of ICS (60,74). Similar loss of bronchoprotection is also observed with salmeterol in AMP (75) and exercise challenge models (76,77), and salmeterol can also reduce the bronchoprotective effect of albuterol (60,74).

Formoterol, in doses ranging from 6 to 24 mg twice daily given to asthma patients already receiving ICS, protects against methacholine-induced bronchoconstriction after the first dose. However, the magnitude of bronchoprotection is significantly reduced after both one and two weeks of treatment (32). The degree of protection afforded by formoterol against AMP is also reduced after one week (78-80).

It is clear that tolerance to bronchoprotection can occur soon after the onset of treatment with either formoterol or salmeterol. An important issue is whether tolerance causes a complete loss of bronchoprotection after prolonged dosing. Larger studies have assessed long-term trends in bronchoprotection loss, and have reassuringly demonstrated that there is still residual bronchoprotection up to 24 weeks (81-83).

Corticosteroid Reversal of LABA Tolerance

Corticosteroids can reverse p2-AR desensitization, but this effect varies with the route of administration and the dose used. For systemic corticosteroids, it has been demonstrated that high doses completely reverse desensitization (84), but that lower doses cause partial reversal only (66). For high doses of ICS, the degree of reversal may differ for bronchodilation and bronchoprotection. For example, after regular treatment with formoterol, a single bude-sonide dose of 1600 mg causes partial reversal of tolerance to the albuterol bronchodilator response (66), but complete reversal of bronchoprotection against AMP (78). It should be noted that while high doses of systemic or inhaled corticosteroids can reverse desensitization, conventional ICS doses do not prevent the development of desensitization (60,74).

Anti-inflammatory Effects

Although LABA are used primarily to cause smooth muscle relaxation, in vitro studies have demonstrated that these drugs also have anti-inflammatory effects (85). The potential for LABA to cause airway anti-inflammatory effects in vivo has therefore also been assessed, and the findings of the key studies are summarized in Table 1. Some of these studies have provided conflicting results, due to a variety of factors, including small sample sizes, differences in the severity of disease in the patients studied and the use of different analytical techniques to evaluate samples.

Table 1 Bronchoscopy Studies That Have Investigated the Anti-inflammatory Effects of Salmeterol or Formoterol

Author year

ICS given with LABA

Mucosal biospy

LABA anti-inflammatory effects

Salmeterol Gardiner, 1994 Li, 1999

Roberts, 1999 Jeffrey, 2002

Lindqvist, 2003 Reid, 2003 Wallin, 2003

Formoterol Wallin, 1999

Wilson, 2001

Yes Yes

No No

No Yes Yes

Yes Yes

Yes Yes

No Yes Yes

No Yes

Yes Yes

Yes No Yes

None Decreased eosinophils (biopsy only) None Decreased neutrophils (BAL and biopsy) None Decreased IL-8 Decreased mast cells (biopsy only)

Decreased eosinophils and mast cells Decreased eosinophils

Abbreviation: BAL, bronchoalveolar lavage.

While it has been reported that salmeterol has no effect on airway inflammation (86-88), there is conflicting evidence that this LABA has an antineutrophil effect (89,90). Formoterol, administered without ICS, appears to exert anti-eosinophil effects (91,92). Clinically it is most relevant to study anti-inflammatory effects when LABA and ICS are administered together. In such patients it has been observed that salmeterol added to ICS causes a reduction in mucosal eosinophils (93) and mast cell levels (94). Furthermore, the addition of salmeterol to ICS reduces submucosal angiogenesis (95), suggesting that combination LABA and ICS treatment decreases the degree of airway remodeling in asthma. Further studies are needed to confirm the synergistic anti-inflammatory effects of LABA and ICS in vivo.

Systemic Effects

Formoterol and salmeterol have the capacity to cause side effects due to systemic absorption. In healthy subjects both of these drugs cause dose-dependent increases in heart rate and blood pressure and decreases in plasma glucose and potassium (96). Cardiac monitoring of asthmatic patients reassuringly shows that LABA do not cause clinically significant cardiac events (97,98). The known pharmacological differences between formoterol and salmeterol in their bronchodilator properties is also observed in their systemic effect profiles, i.e., formoterol is more potent and tends to have a faster onset while the duration is longer for salmeterol (96). The duration of systemic effects with LABA is similar to that observed with SABA (35,99). The prolonged bronchodilator effects of LABA relative to their systemic side effects increases their therapeutic index compared to SABA, which have a similar duration for therapeutic and systemic effects. LABA also cause other predictable p-receptor mediated side effects, similar to those observed with SABA, e.g., tremor (97).

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