Short-Acting Inhaled B2-Agonists: Why, Whom, What, How?

REVIEW Andrzej Emeryk1, Justyna Emeryk-Maksymiuk2 1Department of Pediatric Pulmonology and Rheumatology Medical University in Lublin, Poland 2Chair of Internal Medicine and Department of Internal Medicine in Nursing Medical University in Lublin, Poland Short-acting inhaled b2-agonists: why, whom, what, how? Abstract We showed the present data about the efficacy and safety of inhaled short-acting b2-agonists (SABA), such as salbutamol and fenoterol, in the management of obstructive diseases in children and adults. Our work discusses major mechanisms of action, clinical effects, possible side effects and indications of inhaled SABA. We presented current recommendations for the position of SABA in the therapy of obstructive diseases in children and adults, particularly in asthma and chronic obstructive pulmonary disease. Key words: short-acting b2-agonist, salbutamol, fenoterol, inhalation, nebulization, asthma, COPD Adv Respir Med. 2020; 88: 443–449 Introduction after administration of inhaled salbutamol, but the duration of action does not exceed 4–6 hours Short-acting b2-agonists (SABA) stimulate (Figure 1) [8]. b2-adrenergic receptor (b2-AR). They are called Drugs from this group provide effective b2-mimetics or b2-agonists. First selective SABA protection against exercise-induced bronchoc- widely used in clinical practice appeared more onstriction within 0.5–2.0 hours also against than 50 years ago. They were introduced to the bronchoconstriction triggered by exposure to global market in the following order: terbutaline sensitizing allergen [9, 10]. Clinical studies show (1966 yr.), salbutamol (1968 yr.) and fenoterol more potent bronchodilation and less side effects (1970 yr.) [1]. Next drugs, such as levalbuterol, of R-salbutamol in comparison with racemic sal- reproterol, rimiterol, klenbuterol and pirbuterol, butamol [11–13]. High cost of levalbuterol justi- were introduced afterwards [2–4]. Short-act- fies, however, its administration only in selected ing b2-agonists are selective agonists of b2-AR, clinical conditions [13]. however they differ in their degree of selectivity. Salbutamol (albuterol) is the most used SABA Salbutamol versus fenoterol in the world — in US it took 9th place on the list of prescribed medicines in 2016 (70 million of Two inhaled drugs from SABA group are prescriptions) [5]. According to World Health available in Poland: salbutamol and fenoterol. Organization (WHO) salbutamol ranks among the Table 1 shows their most important properties. most effective and safest medicines essential to Data in the table demonstrate that b2/b1 (se- health care systems [6]. Racemic salbutamol is an lectivity index) stimulation index is 10 times equal (1:1) mixture of R-salbutamol (levalbuterol) greater for salbutamol than fenoterol. Having and S-salbutamol isomers. R-isomer of salbutamol in mind similar stimulation of b2 receptors by is a pharmacologically active compound which both drugs (0.55 salbutamol vs 0.60 fenoterol), exhibits many clinical effects, including potent it means that salbutamol exerts more selective bronchodilation [7]. Suppression of bronchoc- b2-AR stimulation vs fenoterol and both cause onstriction and bronchodilation occur 5 minutes similar bronchodilation. Studies from the 1990s Address for correspondence: Andrzej Emeryk, Department of Pediatric Pulmonology and Rheumatology Medical University in Lublin, Lublin, Poland; e-mail: [email protected] DOI: 10.5603/ARM.a2020.0132 Received: 08.02.2020 Copyright © 2020 PTChP ISSN 2451–4934 www.journals.viamedica.pl 443 Advances in Respiratory Medicine 2020, vol. 88, no. 5, pages 443–449 Figure 1. Effect of single dose of salbutamol, formoterol, and salmeterol on FEV1 value in asthma patients [8]. FEV1 — forced expiratory volume in the first second Table 1. Comparison of short-acting b2-agonists’ (salbutamol and fenoterol vs isoproterenol) ability to stimulate b-adrenergic receptors ( b1, b2, b3) [14, 15] b1 inotropic activity b2 dilatory activity (bron- b3 lipolytic activity (adi- b2/b1 index (atrium) chi)* pocytes) Isoproterenol 1,0 1,0 1,0 1,0 Salbutamol 0,0004 0,55 0,002 1375 Fenoterol 0,005 0,6 0,02 120 *Increase in FEV1 (forced expiratory volume in the first second) ≥ 15% from baseline proved similar or better clinical efficacy and — reduction of capillary permeability (reduc- better safety of salbutamol in comparison with tion of plasma exudate); inhaled fenoterol in different age groups of asth- — suppression of sensory nerves activation; ma patients [16, 17]. Better safety is also a result — improvement of mucociliary clearance; of the fact that salbutamol shows more features — dilatation of pulmonary vascular bed (de- of b2-AR partial agonist than fenoterol. It deter- crease in pO2); mines that asthma patients using salbutamol — increased release of surfactant. have lower risk of death vs patients using feno- They can depend on the polymorphism of terol [17, 18]. It should be stressed that adverse gene encoding b2-AR located on chromosome effects of fenoterol increase in hypoxemia, which 5q31-q32 [20, 21]. Some studies showed rela- occurs during severe and prolonged episode of tionship between response to SABA, course of bronchoconstriction [19]. asthma and the polymorphism of gene encoding b2-AR [22]. It is mainly about 2 polymorphisms: Clinical effects of SABA genotype Arg/Arg at codon 16 of gene encoding b2-AR and Gln/Gln at codon 27 of this gene. It Short-acting b2-agonists in conditions with was revealed that homozygotes for Arg/Arg at bronchoconstriction exert many following clini- codon 16 of gene encoding b2-AR with chronic cal effects [1, 15]: obstructive pulmonary disease (COPD) are pre- — bronchodilation (removal of bronchial disposed to more severe clinical course of the smooth muscles constriction); disease [23]. Similar relationship was shown in — prevention of bronchoconstriction induced patients with cystic fibrosis with altered response by different bronchoconstrictive factors; to SABA [24]. 444 www.journals.viamedica.pl Andrzej Emeryk, Justyna Emeryk-Maksymiuk, Short-acting inhaled b2-agonists: why, whom, what, how? Short-acting b2-agonists usage can be associ- 38], including inhalers transmitting information ated with many side effects described may years to the health care system in real time [39]. ago [25]: tachycardia, skeletal muscle tremor, Salbutamol in pressurised metered-dose hypokalaemia, increased level of lactic acid in inhaler in comparison to other pharmaceutical plasma (lactic acidosis), headaches, hypergly- forms of SABA caemia. Systemic side effects are observed rarely Short-acting b2-agonists have different routes after inhalation administration and increased risk of administration (inhalation, oral and intrave- of cardiovascular side effects appear in patients nous), because they are available in different with comorbid cardiovascular disease, especially pharmaceutical forms. Many forms of salbutamol in the elderly [26, 27]. It is worth mentioning are available [40]: that paradoxical bronchoconstriction after in- — inhalation aerosol (suspension) from pres- halation of SABA occurs in 4.4% of the general surised metered-dose inhaler (pMDI) (chil- population [28]. dren and adults); There are additional possible side effects and — powder from dry powder inhaler (DPI), types: adverse clinical effects when SABA are used in Diskus (children over 4 years and adults), asthma. These effects occur in patients receiving Turbuhaler (children over 3 years and adults) SABA as monotherapy or/and if SABA are used and Easyhaler and (children over 4 years, very often or regularly without inhaled cortico- adults); steroids (ICS). It can lead to increased risk of the — inhalation solution for nebulizers (children following adverse outcomes [29–35]: and adults); — decrease in the number and sensitivity of — sirup (children over 2 years, adults); b2-AR; — tablets (children over 2 years, adults); — diminished bronchial response to SABA or/ — solution for injection (adults). /and LABA; Inhalation is the most effective way of SABA — increased bronchial hyperresponsiveness; therapy in airway diseases. Oral therapy can be — increased allergic reactions and eosinophilic alternative only exceptionally in small children, airway inflammation; who do not accept inhalation or cannot inhale — increased risk for asthma exacerbation (with properly [38]. Additional parenteral therapy regular or frequent use: ≥ 3 SABA canisters/ (salbutamol) is necessary rarely in patients with /year, average 1.7 puffs/day); severe exacerbation of asthma, who do not re- — increased risk of death in patients with asth- spond do proper inhalation therapy [41]. ma (≥ 11 SABA canisters/year); Inhalation formulations of SABA most often — deterioration in spirometric parameters. used are listed in Table 2 [43]. These facts which are known for many years According to table 2, four inhalation formu- and other new clinical evidences for efficacy and lations of salbutamol are available: pMDI, pres- safety of SMART therapy (Single Maintenance surised metered-dose inhaler — breath actuated and Reliver Therapy) changed the perception of pMDI (pMDI-BA), DPI and inhalation solution the role and place of SABA in the management for nebulizers; fenoterol is available only as of asthma in last Global Initiative for Asthma pMDI. The expected therapeutic clinical effects report (GINA) 2019 [36], which will be discussed and probability of side effects can depend on further below. Another way of limiting the SABA the choice of SABA inhalation method. Below overuse

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