Adverse effects of β-agonists

doi:10.1067/mai.2002.129966

Journal of Allergy and Clinical Immunology

Volume 110, Issue 6, Supplement, December 2002, Pages S322-S328

https://doi.org/10.1067/mai.2002.129966 Get rights and content

Abstract

Short-acting β-adrenergic receptor agonists have pharmacologically predictable dose-related and potency-related adverse effects, including tachycardia and tremor, and they also affect serum potassium and glucose. These effects all show tolerance with continued exposure. The potential for arrhythmia is increased by comorbidity and hypoxemia. Nonpharmacologically predictable effects include airway hyperresponsiveness to nonspecific and specific stimuli, including allergen and exercise, and increased airway inflammation. Genetic variants of the β-adrenergic receptor alter susceptibility to adverse effects of β-agonists on airway function. The impact of the enantiomers of β-agonists on adverse effects remains unclear. The two epidemics of asthma death among young people were temporally associated with introduction of potent short-acting β-agonists (isoproterenol and fenoterol) and appear to be related to adverse effects of these drugs on airway function and airway hyperresponsiveness rather than to cardiotoxicity. Compared with short-acting agents, long-acting β-agonists show similar but less pronounced pharmacologically predictable effects, and they have not been shown to increase airway hyperresponsiveness in adults. Postmarketing surveillance studies have not suggested significant adverse effects of long-acting β-agonists on morbidity and mortality. (J Allergy Clin Immunol 2002;110:S322-8.)

Section snippets

Cardiac effects

Mild tachycardia is common when patients are first exposed to β-agonists, even the most recent highly β₂AR-specific agents. In part, tachycardia may result from dilation of peripheral vasculature that reduces venous return, resulting in sympathetic nervous system reflexes and increased inotropic and chronotropic effects. β-Agonists may also stimulate β₂ARs in the cardiac muscle itself, in both the left ventricle and the right atrium, increasing heart rate directly.

The early adrenergic agents,

Pharmacologically predictable effects of SABAs in unusual physiologic circumstances

Several research groups have quite extensively studied the effects of hypoxia in an acute episode of asthma on the response of cardiac muscle and the intact cardiac function as evaluated by electrocardiography. Such effects, which could exaggerate the adverse effects of β-agonists, imply that hypoxemia and hypercapnia should be aggressively treated when high doses of β-agonists are required in acute situations and that perhaps β-agonists should be used with caution in patients with chronic

Increased nonspecific airway responsiveness

Several carefully conducted studies have confirmed that the regular or frequent use of the classic SABAs fenoterol, albuterol, and terbutaline can result in a small increase in AHR, measurable after the drug is withheld for some hours. Responsiveness to nonspecific bronchoconstrictor agents such as histamine or methacholine was increased between 0.5 and 1 doubling dilution by regular use of β-agonist in the majority of studies reviewed.

Animal studies have shown AHR to histamine after treatment

Consequences of adverse effects of SABAs

There seems to be little doubt that the epidemics of both mortality and morbidity (as reflected in hospitalizations and emergency room visits) associated with β-agonists are related to adverse effects on airway responsiveness and not to cardiac or metabolic adverse effects. Increased severity of asthma during regular β-agonist treatment has been manifested as lower lung function as well as increased symptoms, nocturnal symptoms, need for short course of prednisone, and other indicators of a

Pharmacologically predictable effects of LABAs

The pharmacologically predictable effects of LABAs are similar to those seen with SABAs but overall are less substantial.

Nonpharmacologically predictable effects of LABAs

Neither salmeterol nor formoterol has been shown to increase airway responsiveness to either specific stimuli (allergen or exercise) or nonspecific stimuli (histamine, methacholine, saline), except in children, in whom the use of salmeterol as monotherapy led to deterioration of lung function and to AHR.69, 70 Tolerance to the bronchoprotective effects of both salmeterol and formoterol has been repeatedly demonstrated,71, 72 but rebound AHR has not been shown.⁷³ There is no epidemiologic

Conclusions

In summary, the pharmacologically predictable effects of both SABAs and LABAs are not problematic, except perhaps in the presence of hypoxia or comorbidity, and tolerance to these effects occurs readily. LABAs overall show fewer pharmacologically predictable effects than SABAs. Adverse effects on airway responsiveness and inflammation have been shown with regular SABAs but not with LABAs.

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^☆: Reprint requests: Malcolm R. Sears, MB, Firestone Institute for Respiratory Health, St Joseph's Healthcare and Master University, 50 Charlton Ave East, Hamilton, Ontario, L8N 4A6, Canada.

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Nonrespiratory EffectsAdverse effects of β-agonists☆

Abstract

Section snippets

Cardiac effects

Pharmacologically predictable effects of SABAs in unusual physiologic circumstances

Increased nonspecific airway responsiveness

Consequences of adverse effects of SABAs

Pharmacologically predictable effects of LABAs

Nonpharmacologically predictable effects of LABAs

Conclusions

Br J Dis Chest

Respir Med

Lancet

Chest

Br J Dis Chest

Lancet

Ann Allergy Asthma Immunol

Chest

J Allergy Clin Immunol

Chest

Am J Med

J Allergy Clin Immunol

Lancet

J Allergy Clin Immunol

J Allergy Clin Immunol

Chest

Lancet

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

Pulm Pharmacol

J Allergy Clin Immunol

J Allergy Clin Immunol

Lancet

Chest

Chest

Chest

Chest

Respir Med

J Clin Epidemiol

A comparison of the cardiovascular and metabolic effects of formoterol, salbutamol and fenoterol

Eur Respir J

Beta-adrenoceptor responses to inhaled salbutamol in normal subjects

Eur J Clin Pharmacol

Tachyphylaxis to systemic but not to airway responses during prolonged therapy with high dose inhaled salbutamol in asthmatics

Am Rev Respir Dis

High-dose inhaled albuterol in severe chronic airflow limitation

Am Rev Respir Dis

β-Adrenoceptor responses to high doses of inhaled salbutamol in patients with bronchial asthma

Br J Clin Pharmacol

Cardiovascular and hypokalaemic effects of inhaled salbutamol, fenoterol, and isoprenaline

Thorax

Comparison of the effects of prolonged treatment with low and high doses of inhaled terbutaline on beta-adrenoceptor responsiveness in patients with chronic obstructive pulmonary disease

Am Rev Respir Dis

Nonrespiratory Effects
Adverse effects of β-agonists☆