Beta2 agonists effects

Howarth PH, Beckett P, Dahl R. The effect of long-acting beta2-agonists on airway inflammation in asthmatic patients. Respir Med 2000 94 (Suppl F) 22-25. 

Currie GP, Lee DK, Wilson AM. Effects of dual therapy with corticosteroids plus long acting beta2-agonists in asthma. Respir Med. 2005 99 683-694. 

Larj MJ, Bleecker ER. Effects of beta2-agonists on airway tone and bronchial responsiveness. J Allergy Clin Immunol. 2 002 110(Suppl) S304-S312. 

However, it is difficult to extrapolate PC20 changes after treatment with beta2-agonists to the clinical outcome. There is an assumption that if PC20 falls, the patient is more likely to suffer acute attacks when exposed to spasmogens, allergens, and exercise. However, the loss of bronchoprotective effect has not so far been shown to increase morbidity or mortality in asthmatic patients. 

An alternative hypothesis has been proposed to explain why beta2-agonists lose their bronchoprotective effect while retaining a bronchodilator effect. The beta2-agonists currently available for treating asthma consist of racemic mixtures of equal amounts of two stereoisomers, the i -isomer (or L-isomer), which is the beta-adrenoceptor agonist, and the 5-isomer (o-isomer) which is inactive. 

Muscle cramps have been reported in patients taking beta-blockers with partial agonist activity (273) it has been suggested (274) that this might be a beta2-partial agonist effect, although this has not subsequently been... 

Equine Veterinary Journal 29 388-393 Zhang X, Zhu F, Olszewski M et al 1998 Effects of enantiomers of beta2-agonists on ACh release and smooth muscle contraction in the trachea. American Journal of Physiology 274 32-38... 

The functions associated with beta receptors are vasodilation, cardioacceleration, bronchial relaxation, positive inotropic effect, intestinal relaxation, and glycogenolysis and fatty acid release. The beta receptors are responsible for cardiac stimulation and hpolysis. Beta2 receptors are responsible for bronchodilation and vasodepression. Beta2 agonists are especially useful in the treatment of asthma because they produce bronchodilation without causing much cardiac acceleration. 

Laude EA, Morice AH, Grattan TJ (1994) The antitussive effects of menthol, camphor and cineole in conscious guinea-pigs. Pulm Pharmacol 7 179-184 Laursen LC, Lindqvist A, Hepburn T, Lloyd J, Perrett J, Sanders N, Rocchiccioli K (2003) The role of the novel D2/beta2-agonist, Viozan (sibenadet HCl), in the treatment of symptoms of chronic obstructive pulmonary disease Results of a large-scale clinical investigation. Respir Med 97(Suppl A) S23-S33... 

Van Essen-ZandvUet, E. E., Hughes, M. D., Waalkens, H. J., Duiverman, E. J., Pocock, S. J., and Kerrebijn, K. F. (1992). Effects of 22 months of treatment with inhaled corticosteroids and/or beta2-agonists on lung function, airway responsiveness, and symptoms in children with asthma. The Dutch Chronic Non-specific Lung Disease Study Group. Am. Rev. Respir. Dis. 146,547-554. 

Pharmacodynamic interactions are those where the effects of one drug are changed by the presence of another drug at its site of action. Sometimes the drugs directly compete for particular receptors (e.g. beta2 agonists, such as salbutamol, and beta blockers, such as propranolol) but often the reaction is more indirect and involves interference with physiological mechanisms. These interactions are much less easy to classify neatly than those of a pharmacokinetic type. 

Note that all beta2 agonists can cause a fall in serum potassium, which could possibly affect the response of patients to digoxin. The clinical importance of these changes is uncertain but concurrent use should be monitored. Consider monitoring potassium levels if the effects of digoxin seem excessive. 

A recent Cochrane review concluded that cardioselective beta blockers did not produce any significant adverse respiratory effects or reduction in the response to beta2 agonists, and it recommended that cardioselective beta blockers should not be withheld from patients with COPD. Celiprolol (a cardioselective beta blocker) appears to be exceptional in causing mild bronchodilatation in asthmatics and not bronchoconstriction, although it may still produce a reduction in expiratory volume, as seen in the study above, but some caution is still necessary as this requires confirmation. ... 

The bronchoconstrictive effects of the beta blockers can be opposed by beta2 agonist bronchodilators such a salbutamol, but as the manufacturers point out, large doses may be needed and they suggest that ipratropium and intravenous aminophylline may also be needed. ... 

Established interactions. The CSM in the UK advises that, as potentially serious hypokalaemia may result from beta2 agonist therapy, particular caution is required in severe asthma, as this effect may be potentiated by theophylline and its derivatives, corticosteroids, diuretics, and by hypoxia. Hypokalaemia with concurrent use of thiazide and loop diuretics may be reduced or even abolished by the addition of spironolactone or high-dose triamterene. Plasma potassium levels should therefore be monitored in patients with severe asthma. Hypokalaemia may result in cardiac arrhythmias in patients with ischaemic heart disease and may also affect the response of patients to drugs such as the digitalis glycosides and an-tiarrhythmics. 

Beta2 agonists can cause hypokalaemia, particularly when they are given parenterally or by nebulisation. Xanthines such as theophylline can also cause hypokalaemia, and this is a common feature of theophylline toxicity. The potassium-lowering effects of both these groups of drugs are additive. Why some beta agonists lower serum theophylline levels is not known. 

Burgess C, Beasley R, Crane J, Pearce N. Adverse effects of beta2-agonists. In Pauwels R, O Byrne PO, eds. Beta2-Agonists in Asthma Treatment. New York Marcel Dekker, 1997 257-282. 

A possible mechanism to explain the paradoxical loss of asthma control and deterioration in airway hyper-responsiveness associated with regular beta2-agonists has been presented [22 ]. Regular unbalanced monotherapy with salmeterol in patients with mild asthma increases production and storage of brain-derived neurotrophic factor (BDNF), which is a mediator of airway hyper-responsiveness in asthma. Increased BDNF concentrations may therefore underlie the adverse effects of salmeterol monotherapy on airway responsiveness in asthma. 

Korsgaard J, Ledet M. Potential side effects in patients treated with inhaled corticosteroids and long-acting beta2-agonists. Respir Med 2009 103(4) 566-73. 

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